Composition and Method for the Treatment of Diseases Affected by a Peptide Receptor

ABSTRACT

The present invention includes peptidomimetic compound compositions and methods of making and using peptidomimetic compounds to modulate the activity of a peptide receptor for the treatment of one or more of hyperglycemia, insulin resistance, hyperinsulinemia, obesity, hyperlipidemia, hyperlipoproteinemia or other symptoms that relate to the function of the targeted receptor. The peptidomimetic includes an oligo-benzamide compound having at least three optionally substituted benzamides.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 60/894,580 filed Mar. 13, 2007, the contents of which isincorporated by reference herein in its entirety.

TECHNICAL FIELD OF THE INVENTION

The present invention relates in general to the field of peptidomimeticsand specifically to compositions of matter, kits and methods of makingand using the compositions to mimic peptides for the treatment ofdiseases.

BACKGROUND OF THE INVENTION

Without limiting the scope of the invention, its background is describedin connection with compositions that mimic peptides and proteins,methods of making the compositions and using the compositions in thetreatment of diseases. Diabetes mellitus, and associated complications,is the third leading cause of death in the United States and one of themost widespread degenerative diseases. Generally, diabetes mellitusaffects the conversion of sugars and starches into glucose duringdigestion. A pancreatic hormone, insulin, plays a key role in thestorage and use of carbohydrates, protein and fat as a source of energyfor the body. Insulin deficiency is a common and serious pathologiccondition, which may lead to blindness, kidney failure and limbamputations.

Diabetes is a chronic disease characterized by multiple metabolicabnormalities resulting in impaired management of glucose. Generally,diabetes can be classified into insulin-dependent diabetes mellitus(Type I) and non-insulin-dependent diabetes mellitus (Type II).Insulin-dependent diabetes mellitus (Type I) is characterized by theproduction of little or no insulin by the pancreas and requires dailyinsulin injections for treatment. Non-insulin-dependent diabetesmellitus (Type II) is characterized by a combination of reduced insulinresponsiveness and a relative deficiency of insulin production. The mostcommon form of diabetes is Type II, which affects about 90-95% ofdiabetic patients.^(1,2) The treatment of non-insulin-dependent diabetesmellitus (Type II) is more challenging due to the complex pathogenesisinvolving progressive development of insulin resistance and deficiencyin insulin secretion.⁴

The major pancreatic islet hormones, glucagon, insulin and somatostatin,interact with and/or originate from specific pancreatic cell types tomodulate the secretory response. Glucagon is derived from the processingof proglucagon, which is in itself derived from the 360 base pairpreproglucagon gene. However, proglucagon also contains two otherdiscrete and highly homologous peptide regions designated glucagon,glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2). The30-amino acid glucagon-like peptide-1 (GLP-1) has been shown to functionas a stimulus of insulin secretion.

GLP-1¹⁴ is produced by intestinal L-cells through the proteolyticalprocessing of preproglucagon.⁵⁻⁸ GLP-1 functions by acting on a cognatepeptide receptor (GLP-1R). In addition to enhancing insulin secretionand restoring glucose sensitivity to the islets, this peptide alsoincreases expression of the glucose transporter and glucokinase.¹⁴⁻¹⁶

Additionally, GLP-1 displays numerous beneficial effects on regulatingβ-cell mass by stimulating replication and growth of existing β-cells,inhibiting apoptosis, and triggering neogenesis of new β-cells from ductprecursor cells.^(17,18) GLP-1 also inhibits secretion of glucagon whichis often found in abnormally high concentrations in diabeticpatients.^(19,20) Apart from these effects, it is a potent inhibitor ofgastric emptying,²¹ and causes an inhibition of appetite withsuppression of food intake. This results in a decrease in body weight,making GLP-1 an efficient treatment of obesity which often accompaniesdiabetes.^(22,23) Since all these GLP-1 induced functions are extremelyfavorable to the treatment of Type II diabetes, therapies based on thispeptide hold considerable clinical promise.²⁴

For example, one method for regulation of glucose and lipid metabolism,generally to reduce hyperglycemia, insulin resistance, obesity,hyperlipidemia, and hyperlipoproteinemia, is taught in U.S. Pat. No.7,157,429 issued to Bachovchin, et al. entitled Method of regulatingglucose metabolism and reagents related thereto. It includesdipeptidylpeptidase inhibitors, which are able to inhibit theproteolysis of GLP-1 and accordingly increase the plasma half-life ofthat hormone. The subject inhibitors may be peptidyl, peptidomimetic(e.g. boronyl peptidomimetics), or non-peptidyl nitrogen containingheterocycles.

Conventional methods for identifying such inhibitors include thepreparation and screening of chemical libraries to discover leadcompounds although often with little success.

SUMMARY OF THE INVENTION

The present inventors recognized that a rational design approachprovides a compelling alternative to conventional methods. The presentinventors recognized that based on a structural knowledge of theinterface of protein complexes. The present inventors recognized thatα-helix mimetics may be used to modulate protein-protein orprotein-peptide interaction. In particular, synthetic scaffolds thatmimic key elements found in the interface can potentially lead todevelop potent small molecule modulators. The present inventorsrecognized that mimetics can be used to interact with complexes ofvarious types. For example the mimetics can be used to interact with apeptide receptor, including a GLP-1 receptor for diabetes application.The present inventors also recognized that the mimetics of the presentinvention may be used to interact with other cellular proteins, surfaceproteins and protein complexe.

The present inventors recognized that numerous drugs (e.g., insulin,insulin-sensitizing drugs, and cancer treatment drugs) are employed totreat diabetes, but they do not address the issue of dying pancreaticβ-cells, a fundamental dysfunction observed in diabetes. Furthermore,treatment with these drugs tends to increase body weight and oftencarries an enhanced risk of triggering accidental hypoglycemic episodeswhere blood glucose levels are temporarily too low.

The present inventors recognized that glucagon-like peptide-1 (GLP-1)agonists have unique antidiabetic functions (e.g., by stimulatinginsulin secretion, restoring glucose sensitivity to the pancreaticislets, regulating β-cell mass, and suppressing glucagon secretion).However, as a result of their peptide structure the currently knownagonists are susceptible to rapid enzymatic degradation, and requirei.v. or s.c. administration. In addition, there is a risk of developingan immune response against these peptide therapeutics.

The present inventors recognized a need for stable small moleculespossessing the capability to activate the GLP-1 receptor (GLP-1R) butlacking the limitations of the peptide structure. The present inventionprovides a class of small molecules that are stable and capable ofactivating the GLP-1 receptor (GLP-1R) but lacking the limitations ofthe peptide structure. These small molecules include α-helix mimeticsthat represent helical segments in GLP-1.

The present invention provides a method of modifying glucose metabolismin a glucose intolerant subject by administering an oligo-benzamidepeptidomimetic to the subject suspected of being glucose intolerant. Theoligo-benzamide peptidomimetic compound includes at least two optionallysubstituted benzamides, with each of the substituted benzamides havingone or more substitutions on a benzene ring. The oligo-benzamidepeptidomimetic compound modifies glucose metabolism by reducing one ormore of hyperglycemina, insulin resistance, glucose intolerance,obesity, hyperlipidemia, or hyperlipoproteinemia.

Another embodiment of the present invention is the addition of a thirdoptionally substituted benzamide connected to one of the at least twooptionally substituted benzamides, and the third optionally substitutedbenzamide may include one or more substitutions on a benzene ring. Thepresent invention also provides an oligo-benzamide peptidomimeticcompound that includes at least two optionally substituted benzamideswith one or more substitutions on a benzene ring.

The present invention also provides a peptidomimetic compound that atleast partially activates or inhibits a peptide receptor. Thepeptidomimetic compound includes a tris-benzamide peptidomimetic, threeoptionally substituted benzamides and one or more substituted groupsattached to each of the substituted benzamides individually by achemical bond including ether, thioether, amine, aminde, carbamate,urea, and carbon-carbon (single, double, and triple) bonds.

The present invention provides a method for treating a subject thatwould benefit from stimulating or inhibiting a peptide receptor byadministering to the subject an oligo-benzamide peptidomimetic compoundcomprising more than two optionally substituted benzamides and one ormore substituted groups attached to each of the substituted benzamidesindividually by a chemical bond including ether, thioether, amine,amide, carbamate, urea, and carbon-carbon (single, double, and triple)bonds. The pharmaceutical peptidomimetic compound may be adapted fororal, dermatological, transdermal or parenteral administration.

Peptide receptors typically reside on the cell membrane and serve asrecognition sites of peptide hormones/transmitters (such as GLP-1).These peptides may be either locally produced (within the same tissue)or may be generated elsewhere in the body and are transported to thetarget tissue via the blood stream (such as GLP-1). Binding of thepeptide to its cognate receptor modulates a wide range of cellularfunctions such as intracellular signaling, growth, apoptosis, secretion,differentiation, electrical excitation or inhibition, gene expression,and many others.

Peptide receptors are known to comprise two major superfamilies. One ofthese includes single transmembrane domain proteins which often functionas dimers, e.g. receptors responding to insulin, epidermal growthfactor, and erythropoietin. Another receptor superfamily comprisesG-protein coupled receptors (GPCRs). Within the latter group, peptidereceptors are mostly found in the class A (rhodopsin-like) and class Bsubfamilies. The GLP-1R falls within the class B GPCR subfamily.

Endogenous peptide ligands which act on peptide receptors typically havea distinct tertiary structure that enables these molecules toselectively recognize receptors with high affinity and to modulate theirfunctions. One defining structural feature of such peptides areα-helices, i.e. structures in which the amino acid side chains areplaced in a circular orientation with a characteristic angle of 100°between adjacent residues. For example, this structural hallmark playsan important role in the function of GLP-1 and of other ligands that acton class B GPCRs.

The present invention provides a pharmaceutical peptidomimeticcomposition for treating one or more glucose metabolism diseases (e.g.,hyperglycemia, insulin resistance, hyperinsulinemia, obesity,hyperlipidemia, hyperlipoproteinemia or a combination thereof) and othermedical symptoms related to peptide receptors. The pharmaceuticalpeptidomimetic composition includes a therapeutically effective amountof an oligo-benzamide peptidomimetic compound or a salt, a solvate, or aderivative thereof having an oligo-benzamide peptidomimetic compound andone or more pharmaceutically acceptable carriers. The oligo-benzamidepeptidomimetic compound includes more than two optionally substitutedbenzamides (e.g., substituted and/or non-substituted benzamides) and oneor more substituted groups attached to each of the substitutedbenzamides individually by a chemical bond including ether, thioether,amine, amide, carbamate, urea, and carbon-carbon (single, double, andtriple) bonds.

The present invention provides a peptidomimetic compound having theformulas:

The present invention provides an oligo-benzamide peptidomimeticcompound containing at least two optionally substituted benzamides. Eachof the optionally substituted benzamides may be optionally substitutedon the benzene ring with one or more substitutions.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the features and advantages of thepresent invention, reference is now made to the detailed description ofthe invention along with the accompanying figures and in which:

FIGS. 1A-1E are images of the structure of α-helix peptidomimeticcompounds that represent one α-helical face of a peptide;

FIGS. 2A and 2B are graphs of the biological activity of the α-helixpeptidomimetic compounds;

FIGS. 3A and 3B are helix wheel plots of the residues in GLP-1;

FIG. 4 is a synthesis scheme for the preparation of peptidomimeticcompounds of the present invention that represent one α-helical face ofa peptide;

FIGS. 5A and 5B are images that illustrate various additionalpeptidomimetic compounds of the present invention that represent oneα-helical face of a peptide;

FIGS. 6A-6C are images that illustrate the structures of α-helixpeptidomimetic compounds that represent two α-helical faces of apeptide;

FIG. 7 is a scheme for the synthesis of peptidomimetic compounds of thepresent invention that represent two α-helical faces of a peptide;

FIGS. 8A and 8B illustrate the structures of various additionalpeptidomimetic compounds of the present invention that represent twoα-helical faces of a peptide;

FIGS. 9A-9E are schematics of the peptide chain of GLP-1 in whichincreasing segments are substituted by peptidomimetic structure;

FIG. 10 is a scheme for the synthesis of additional α-helixpeptidomimetic compounds;

FIG. 11A is an image of a bis-benzamide structure that is used togenerate α-helix peptidomimetic compounds of the present invention;

FIGS. 11B and 11C are images of the energy-minimized structure of anα-helix peptidomimetic compound;

FIG. 12 is a scheme for the synthesis of another α-helix peptidomimeticcompound of the present invention;

FIGS. 13A-13N are images of various structures of substituted groupsthat may be placed at the R positions of the α-helix peptidomimeticcompounds;

FIG. 14 is the primary structure of GLP-1;

FIG. 15 is an image of various optionally substituted oligo-benzamideα-helix peptidomimetic compounds;

FIGS. 16A-16K are structures of various α-helix peptidomimeticscompounds;

FIGS. 17A-17M are structures of another subset of the α-helixpeptidomimetics compounds described in the current invention;

FIGS. 18A-18K are structures of additional subset of the α-helixpeptidomimetics compounds described in the current invention; and

FIGS. 19A-19E are structures of another subset of the α-helix mimeticscompounds described in the current invention.

DETAILED DESCRIPTION OF THE INVENTION

While the making and using of various embodiments of the presentinvention are discussed in detail below, it should be appreciated thatthe present invention provides many applicable inventive concepts thatcan be embodied in a wide variety of specific contexts. The specificembodiments discussed herein are merely illustrative of specific ways tomake and use the invention and do not delimit the scope of theinvention.

To facilitate the understanding of this invention, a number of terms aredefined below. Terms defined herein have meanings as commonly understoodby a person of ordinary skill in the areas relevant to the presentinvention. Terms such as “a”, “an” and “the” are not intended to referto only a singular entity, but include the general class of which aspecific example may be used for illustration. The terminology herein isused to describe specific embodiments of the invention, but their usagedoes not delimit the invention, except as outlined in the claims.

As used herein an “Agonist” is a molecule that selectively binds to aspecific receptor and triggers a response. Generally, an Agonist mimicsthe action of an endogenous biochemical molecule (e.g., hormone orneurotransmitter) that binds to the receptor. As used herein an“Antagonist” binds to the receptor but does not activate the receptorand actually blocks it from activation by agonists. As used herein a“Partial Agonist” activates a receptor, but only produces a partialresponse compared to a full agonist. As used herein a “Co-agonist” workswith other co-agonists to produce the desired effect together. As usedherein, an “Inverse Agonist” provides responses that inhibitconstitutive, ligand-independent basal activity of a receptor and thusshows a function which is in some way opposite to that of Agonists.

As used herein, the term “Alkyl” denotes branched or unbranchedhydrocarbon chains, having between about 1-20 carbons, with “lowerAlkyl” denoting branched or unbranched hydrocarbon chains, havingbetween about 1-10 carbons. Non-limiting examples include methyl, ethyl,propyl, n-propyl, isopropyl, butyl, n-butyl, sec-butyl, isobutyl,t-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, 2-methylpentyl,hexyl, heptyl, octyl, nonyl, decyl, octadecyl and so on. Alkyl includescycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl. These groups can be optionally substituted with one or morefunctional groups which are attached commonly to such chains, such as,hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano,alkylthio, heterocyclyl, aryl, heteroaryl, carboxyl, carbalkoyl,carboxamidyl, alkoxycarbonyl, carbamoyl, alkyl, alkenyl, alkynyl, nitro,amino, alkoxy, amido, imino, imido, guanidino, hydrazido, aminoxy,alkoxyamino, and the like to form alkyl groups such as trifluoro methyl,3-hydroxyhexyl, 2-carboxypropyl, 2-fluoroethyl, carboxymethyl,cyanobutyl and the like.

As used herein, the term “Aryl” denotes a chain of carbon atoms whichform at least one aromatic ring having between about 4-20 carbon atoms,such as phenyl, naphthyl, biphenyl, anthracenyl, pyrenyl,tetrahydronaphthyl, and so on, any of which may be optionallysubstituted. Aryl also includes arylalkyl groups such as benzyl,phenethyl, and phenylpropyl. Aryl includes a ring system containing anoptionally substituted 5 or 6-membered carbocyclic aromatic ring, saidsystem may be bicyclic, polycyclic, bridge, and/or fused. The system mayinclude rings that are aromatic, or partially or completely saturated.Examples of ring systems include phenyl, naphtyl, biphenyl, anthracenyl,pyrenyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, thiophenyl,pyridyl, pyrrolyl, furanyl, quinolyl, quinolinyl, indenyl, pentalenyl,1,4-dihydronaphthyl, indanyl, benzimidazolyl, benzothiophenyl, indolyl,benzofuranyl, isoquinolinyl, and so on. The group may be substitutedwith one or more functional groups which are attached commonly to suchchains, such as hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio,cyano, cyanoamido, alkylthio, heterocycle, aryl, heteroaryl, carboxyl,carbalkoyl, carboxamidyl, alkoxycarbonyl, carbamyl, alkyl, alkenyl,alkynyl, nitro, amino, alkoxy, amido, imino, imido, guanidino,hydrazido, aminoxy, alkoxyamino and the like to form aryl groups such asbiphenyl, iodobiphenyl, methoxybiphenyl, anthryl, bromophenyl,iodophenyl, chlorophenyl, hydroxyphenyl, methoxyphenyl, formylphenyl,acetylphenyl, trifluoromethylthiophenyl, trifluoromethoxyphenyl,alkylthiophenyl, trialkylammoniumphenyl, aminophenyl, amidophenyl,thiazolylphenyl, oxazolylphenyl, imidazolylphenyl,imidazolylmethylphenyl, and the like.

As used herein, the term “Alkenyl” includes optionally substitutedstraight chain and branched hydrocarbons having between about 1-50carbons as above with at least one carbon-carbon double bond (sp²).Alkenyls include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (orallyl), isopropenyl (or 1-methylvinyl), but-1-enyl, but-2-enyl,butadienyls, pentenyls, hexa-2,4-dienyl, and so on. Hydrocarbons havinga mixture of double bonds and triple bonds, such as 2-penten-4-ynyl, aregrouped as alkynyls herein. Alkenyl includes cycloalkenyl. Cis and transor (E) and (Z) forms are included within the invention. These groups canbe optionally substituted with one or more functional groups which areattached commonly to such chains, such as, hydroxyl, bromo, fluoro,chloro, iodo, mercapto or thio, cyano, alkylthio, heterocyclyl, aryl,heteroaryl, carboxyl, carbalkoyl, carboxamidyl, alkoxycarbonyl,carbamoyl, alkyl, alkenyl, alkynyl, nitro, amino, alkoxy, amido, imino,imido, guanidino, hydrazido, aminoxy, alkoxyamino and the like to formalkyl groups such as trifluoro methyl, 3-hydroxyhexyl, 2-carboxypropyl,2-fluoroethyl, carboxymethyl, cyanobutyl and the like.

As used herein, the term “Alkynyl” includes optionally substitutedstraight chain and branched hydrocarbons having between about 1-50carbons as above with at least one carbon-carbon triple bond (sp).Alkynyls include ethynyl, propynyls, butynyls, and pentynyls.Hydrocarbons having a mixture of double bonds and triple bonds, such as2-penten-4-ynyl, are grouped as alkynyls herein. Alkynyl does notinclude cycloalkynyl. These groups can be optionally substituted withone or more functional groups which are attached commonly to suchchains, such as, hydroxyl, bromo, fluoro, chloro, iodo, mercapto orthio, cyano, alkylthio, heterocyclyl, aryl, heteroaryl, carboxyl,carbalkoyl, carboxamidyl, alkoxycarbonyl, carbamoyl, alkyl, alkenyl,alkynyl, nitro, amino, alkoxy, amido, imino, imido, guanidino,hydrazido, aminoxy, alkoxyamino and the like to form alkyl groups suchas trifluoro methyl, 3-hydroxyhexyl, 2-carboxypropyl, 2-fluoroethyl,carboxymethyl, cyanobutyl and the like.

As used herein, the term “Alkoxy” includes an optionally substitutedstraight chain or branched alkyl group having between about 1-50 carbonswith a terminal oxygen linking the alkyl group to the rest of themolecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy,t-butoxy, pentoxy and so on. Alkyoxy also includes any substituted alkylgroup connected by an ether linkage, such as aminobutoxy, carboxyethoxy,hydroxyethoxy and so on.

“Aminoalkyl”, “thioalkyl”, and “sulfonylalkyl” are analogous to alkoxy,replacing the terminal oxygen atom of alkoxy with, respectively, NH (orNR), S, and SO₂. Heteroalkyl includes alkoxy, aminoalkyl, thioalkyl, andso on.

As used herein, the term “pharmaceutically acceptable” means that whichis useful in preparing a pharmaceutical composition that is generallysafe, non-toxic and neither biologically nor otherwise undesirable andincludes that which is acceptable for veterinary use as well as humanpharmaceutical use.

As used herein, the term “Pharmaceutically Acceptable Salts” means saltsof compounds of the present invention which are pharmaceuticallyacceptable, as defined above, and which possess the desiredpharmacological activity. Such salts include acid addition salts formedwith inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or withorganic acids such as acetic acid, propionic acid, hexanoic acid,heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartatic acid, citric acid, benzoic acid,o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,p-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid and the like.

Pharmaceutically Acceptable Salts also include base addition salts,which may be formed when acidic protons present are capable of reactingwith inorganic or organic bases. Acceptable inorganic bases includesodium hydroxide, sodium carbonate, potassium hydroxide, aluminumhydroxide and calcium hydroxide. Acceptable organic bases includeethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine and the like.

As used herein, the term “Subject” includes humans, non-human mammals(e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer,monkeys and the like) and non-mammals (e.g., birds, reptiles and thelike).

As used herein, the term “Treatment” or “Treating” means anyadministration of a compound which at least partially prevents thedisease from occurring in a subject who may be predisposed to thedisease but does not yet experience or display the pathology orsymptomatology of the disease, arrests further development or inhibitsthe disease in a subject that is experiencing or displaying thepathology or symptomatology of the disease, or ameliorates the diseasein a subject that is experiencing or displaying the pathology orsymptomatology of the disease. The term “Disease” is used here todescribe a condition that is characterized by suboptimal function ofphysiological (including mental) processes, and is used here in itswidest sense including undesirable cosmetic appearance.

The present invention provides a method of modifying glucose metabolismin a diabetic subject by administering an oligo-benzamide peptidomimeticto the subject suspected of being diabetic, or to be at risk of becomingdiabetic. The oligo-benzamide peptidomimetic compound includes at leasttwo optionally substituted benzamides, with each of the substitutedbenzamides having one or more substitutions on a benzene ring. Theoligo-benzamide peptidomimetic compound modifies glucose metabolism byreducing one or more of hyperglycemia, insulin resistance, glucoseintolerance, obesity, hyperlipidemia, hyperlipoproteinemia, and othermedical symptoms related to peptide receptors. Although theoligo-benzamide peptidomimetic compound as illustrated includes 2 or 3optionally substituted benzamides, the number of optionally substitutedbenzamides may be 4, 5, 6, 7, 8, 9, 10 or more. In addition, linkagesbetween the optionally substituted benzamides may be varied as necessaryincluding ester, thioester, thioamide, trans-ethylene, ethyl, methyloxy,methylamino, hydroxyethyl, carbamate, urea, imide, hydrozido, aminoxy,or other linkages known to the skilled artisan. And, the oligo-benzamidepeptidomimetic compound may be attached to amino acids, oligopeptides,optionally substituted alkyl, or other structures known to the skilledartisan.

The substitutions on the substituted benzamide are generally on abenzene ring and may be on the 2, 3, 4, 5, or 6 position of each of thebenzene rings. The substitutions may be at the same position on each ofthe benzamide rings but may also be at different positions on each ofthe benzene rings. The one or more substitutions may include anynecessary functional groups to achieve the desired effect. For example,the one or more substitutions are connected to the benzamide ring by achemical linkage including ether, thioether, amine, amide, carbamate,urea, and carbon-carbon (single, double, and triple) bonds, and the oneor more substitutions comprise one or more optionally substituted alkylgroups, lower alkyl groups, alkoxy groups, alkoxyalkyl groups, hydroxygroups, hydroxyalkyl groups, alkenyl groups, amino groups, imino groups,nitrate groups, alkylamino groups, nitroso groups, aryl groups, biarylgroups, bridged aryl groups, fused aryl groups, alkylaryl groups,arylalkyl groups, arylalkoxy groups, arylalkylamino groups, cycloalkylgroups, bridged cycloalkyl groups, cycloalkoxy groups, cycloalkyl-alkylgroups, arylthio groups, alkylthio groups, alkylsulfinyl groups,alkylsulfonyl groups, arylsulfonyl groups, arylsulfinyl groups,caboxamido groups, carbamoyl groups, carboxyl groups, carbonyl groups,alkoxycarbonyl groups, halogen groups, haloalkyl groups, haloalkoxygroups, heteroayl, heterocyclic ring, arylheterocyclic ring,heterocyclic compounds, amido, imido, guanidino, hydrazido, aminoxy,alkoxyamino, alkylamido, carboxylic ester groups, thioethers groups,carboxylic acids, phosphoryl groups or combination thereof.

The present invention also provides an oligo-benzamide peptidomimeticcompound that includes at least two optionally substituted benzamides,with each of the substituted benzamides having one or more substitutionson a benzene ring. The one or more substitutions are individuallyattached to the benzene rings of the oligo-benzamide peptidomimeticcompound by a chemical linkage including ether, thioether, amine, amide,carbamate, urea, and carbon-carbon (single, double, and triple) bonds.The one or more substitutions generally include one or more optionallysubstituted alkyl groups, lower alkyl groups, alkoxy groups, alkoxyalkylgroups, hydroxy groups, hydroxyalkyl groups, alkenyl groups, aminogroups, imino groups, nitrate groups, alkylamino groups, nitroso groups,aryl groups, biaryl groups, bridged aryl groups, fused aryl groups,alkylaryl groups, arylalkyl groups, arylalkoxy groups, arylalkylaminogroups, cycloalkyl groups, bridged cycloalkyl groups, cycloalkoxygroups, cycloalkyl-alkyl groups, arylthio groups, alkylthio groups,alkylsulfinyl groups, alkylsulfonyl groups, arylsulfonyl groups,arylsulfinyl groups, caboxamido groups, carbamoyl groups, carboxylgroups, carbonyl groups, alkoxycarbonyl groups, halogen groups,haloalkyl groups, haloalkoxy groups, heteroayl, heterocyclic ring,arylheterocyclic ring, heterocyclic compounds, amido, imido, guanidino,hydrazido, aminoxy, alkoxyamino, alkylamido, carboxylic ester groups,thioethers groups, carboxylic acids, phosphoryl groups or combinationthereof.

The substitutions may be on a single first face of the oligo-benzamidepeptidomimetic compound to form an α-helix oligo-benzamidepeptidomimetic compound or on two faces of the oligo-benzamidepeptidomimetic compound to form an amphiphilic α-helix oligo-benzamidepeptidomimetic compound.

A third optionally substituted benzamide with one or more optionalsubstitutions on a benzene ring may be connected to one of the at leasttwo optionally substituted benzamides. The present invention alsoprovides an oligo-benzamide peptidomimetic compound having one or moresubstitutions on a first face and a second face of the oligo-benzamidepeptidomimetic compound, wherein an amphiphilic α-helix oligo-benzamidepeptidomimetic is formed. The one or more substitutions are at one ormore positions of the oligo-benzamide peptidomimetic selected from an iposition, an i+2 position, an i+3 position, an i+4 position, an i+5position, and an i+7 position of a target peptide hormone. For example,one of the one or more substitutions correspond to an i position, one ofthe one or more substitutions correspond to an i+3 position or an i+4position, and one of the one or more substitutions correspond to an i+7position of a target peptide hormone.

The present invention provides a pharmaceutical peptidomimeticcomposition for treating one or more of glucose metabolism diseases(e.g., hyperglycemia, insulin resistance, hyperinsulinemia, obesity,hyperlipidemia, hyperlipoproteinemia or a combination thereof) and othermedical symptoms based on peptide receptors. The pharmaceuticalpeptidomimetic composition includes a therapeutically effective amountof an oligo-benzamide peptidomimetic compound or a salt, a solvent, or aderivative thereof based on an oligo-benzamide peptidomimetic compound,and one or more pharmaceutically acceptable carriers. For example, thetris-benzamide peptidomimetic compound includes three optionallysubstituted benzamides and one or more substituted groups attached toeach of the substituted benzamides individually by a chemical linkageincluding ether, thioether, amine, amide, carbamate, urea, andcarbon-carbon (single, double, and triple) bonds. The pharmaceuticalpeptidomimetic composition may also include one or more additionalactive ingredients, diluents, excipients, active agents, lubricants,preservatives, stabilizers, wetting agents, emulsifiers, salts forinfluencing osmotic pressure, buffers, colorings, flavorings, aromaticsubstances, penetration enhancers, surfactants, fatty acids, bile salts,chelating agents, colloids and combinations thereof. The pharmaceuticalpeptidomimetic compound may be adapted for oral, dermatological,transdermal or parenteral administration, in the form of a solution, aemulsions, a liposome-containing formulation, a tablet, a capsule, a gelcapsule, a liquid syrup, a soft gel, a suppository, an enema, a patch,an ointment, a lotion, a cream, a gel, a drop, a spray, a liquid or apowder.

The present invention provides peptidomimetic compounds having theformulas:

wherein each of the formulas may be substituted as follows. X mayindependently be a C, a N, a O, a S, a H, —CH₂CH₂—, —CH═CH—, —C≡C—,—NH—, —NR—, —NH—NH—, —NH(CH₂)_(n)NH, —NR(CH₂)_(n)NR′— —NR—NR′—, —NH—O—,—NR—O—, —NH(CH₂)_(n)O—, —NR(CH₂)_(n)O—, —NH(CH₂)_(n)S—, —NR(CH₂)_(n)S—,—O(CH₂)_(n)O—, —O(CH₂)_(n)S—, —S(CH₂)_(n)S—, —CO—, —CO₂—, —COS—, —CONH—,—CONR—, —OC(O)NH—, —NHCONH—, —CONHCO—, —CO(CH₂)_(n)CO—, or combinationthereof; and Y may be independently a N, a O, a S or 2 H's. And, n is 0,1, 2, 3, 4, 5, 6, 7 etc.

R1, R2, R3, R4, R′1, R′2, R′3, R′4, R″1, R″2, R″3, and R″4, compriseindependently a H, optionally substituted alkyl, lower alkyl, alkoxy,alkoxyalkyl, hydroxy, hydroxyalkyl, alkenyl, amino, imino, nitrate,alkylamino, dialkylamino, nitro, nitroso, aryl, biaryl, polycyclicaromatic, alkylaryl, arylalkyl, arylalkoxy, arylalkylamino, cycloalkyl,bridged cycloalkyl, cycloalkoxy, cycloalkyl-alkyl, arylthio, alkylthio,alkylsulfinyl, alkylsulfonyl, arylsulfonyl, arylsulfinyl, caboxamido,carbamoyl, carboxyl, carbonyl, alkoxycarbonyl, halogen, haloalkyl,haloalkoxy, heteroayl, heterocyclic ring, arylheterocyclic ring,heterocyclic compounds, amido, imido, guanidino, hydrazido, aminoxy,alkoxyamino, alkylamido, urea, carboxylic ester, thioether, carboxylicacid, phosphoryl groups, polycyclic aromatic substituted with a OH, NH₂,SH, F, Cl, Br, I, NHR, NRR′, CN₃H₄, a N, a O, a S, a H, or combinationthereof.

Alternatively, R1, R2, R3, R4, R′1, R′2, R′3, R′4, R″1, R″2, R″3, andR″4 may be one or more of the following:

where Z is an OH, NH₂, SH, F, Cl, Br, I. W is an OH, an OR, a NH₂, aNHR, a NRR′ (R, R′ are alkyl groups), and an imine (C(NH)R₁R₂. Forexample, when R1 is a NH₂ and R₂ is a NH the imine is actually aguanidine group), and n is 0, 1, 2, 3, 4, 5, 6, 7 etc.

“A” may be a substituent (R1, R2, R3, R4, R′1, R′2, R′3, R′4, R″1, R″2,R″3, or R″4), an acetyl, a Boc (t-butoxycarbonyl), a Fmoc(9-fluorenylmethoxycarbonyl), a Cbz (benzyloxycarbonyl), an Aloc(allyloxycarbonyl), an alkyl group, an alanine, an arginine, anasparagine, an aspartic acid, a cysteine, a glutamic acid, a glutamine,a glycine, a histidine, an isoleucine, a leucine, a lysine, amethionine, a phenylalanine, a proline, a serine, a threonine, atryptophan, a tyrosine, a valine, dipeptide, tripeptide, tetrapeptide,pentapeptide, oligopeptide, dipeptide which has greater than 50%sequence homology to a portion of the GLP-1 sequence SEQ. ID. NO.: 1,tripeptide which has greater than 50% sequence homology to a portion ofthe GLP-1 sequence SEQ. ID. NO.: 1, tetrapeptide which has greater than50% sequence homology to a portion of the GLP-1 sequence SEQ. ID. NO.:1, pentapeptide which has greater than 50% sequence homology to aportion of the GLP-1 sequence SEQ. ID. NO.: 1, oligopeptide whichconsists of no greater than 30 amino acids and has greater than 50%sequence homology to a portion of the GLP-1 sequence SEQ. ID. NO.: 1, asseen in FIG. 14.

In addition “A” may be a linker as seen below

connected to a substituent (R1, R2, R3, R4, R′1, R′2, R′3, R′4, R″1,R″2, R″3, or R″4), an alanine, an arginine, an asparagine, an asparticacid, a cysteine, a glutamic acid, a glutamine, a glycine, a histidine,an isoleucine, a leucine, a lysine, a methionine, a phenylalanine, aproline, a serine, a threonine, a tryptophan, a tyrosine, a valine,dipeptide, tripeptide, tetrapeptide, pentapeptide, oligopeptide,dipeptide which has greater than 50% sequence homology to a portion ofthe GLP-1 sequence SEQ. ID. NO.: 1, tripeptide which has greater than50% sequence homology to a portion of the GLP-1 sequence SEQ. ID. NO.:1, tetrapeptide which has greater than 50% sequence homology to aportion of the GLP-1 sequence SEQ. ID. NO.: 1, pentapeptide which hasgreater than 50% sequence homology to a portion of the GLP-1 sequenceSEQ. ID. NO.: 1, oligopeptide which consists of no greater than 30 aminoacids and has greater than 50% sequence homology to a portion of theGLP-1 sequence SEQ. ID. NO.: 1.

“B” may be a substituent (R1, R2, R3, R4, R′1, R′2, R′3, R′4, R″1, R″2,R″3, or R″4), an alanine, an arginine, an asparagine, an aspartic acid,a cysteine, a glutamic acid, a glutamine, a glycine, a histidine, anisoleucine, a leucine, a lysine, a methionine, a phenylalanine, aproline, a serine, a threonine, a tryptophan, a tyrosine, a valine, analkyl group, dipeptide, tripeptide, tetrapeptide, pentapeptide,oligopeptide, a dipeptide which has greater than 50% sequence homologyto a portion of the GLP-1 sequence SEQ. ID. NO.: 1, a tripeptide whichhas greater than 50% sequence homology to a portion of the GLP-1sequence SEQ. ID. NO.: 1, a tetrapeptide which has greater than 50%sequence homology to a portion of the GLP-1 sequence SEQ. ID. NO.: 1, apentapeptide which has greater than 50% sequence homology to a portionof the GLP-1 sequence SEQ. ID. NO.: 1, an oligopeptide which consists ofno greater than 30 amino acids and has greater than 50% sequencehomology to a portion of the GLP-1 sequence SEQ. ID. NO.: 1.

In addition “B” may be a dipeptide which has greater than 50% sequencehomology to a portion of the GLP-1 sequence SEQ. ID. NO.: 1, atripeptide which has greater than 50% sequence homology to a portion ofthe GLP-1 sequence SEQ. ID. NO.: 1, a tetrapeptide which has greaterthan 50% sequence homology to a portion of the GLP-1 sequence SEQ. ID.NO.: 1, a pentapeptide which has greater than 50% sequence homology to aportion of the GLP-1 sequence SEQ. ID. NO.: 1, an oligopeptide whichconsists of no greater than 30 amino acids and has greater than 50%sequence homology to a portion of the GLP-1 sequence SEQ. ID. NO.: 1,connected to compounds M1 to M12 of FIG. 15, or 19A of FIG. 19.

In addition “B” may be a linker as seen below

connected to a substituent (R1, R2, R3, R4, R′1, R′2, R′3, R′4, R″1,R″2, R″3, or R″4), an alkyl group, or one or more compounds M1 to M12 ofFIG. 15, or 19A of FIG. 19.

The present invention provides an oligo-benzamide peptidomimeticcompound having the formula:

wherein R2, R3, R4, R5, R′2, R′3, R′4, R′5, R″2, R″3, R″4, and R″5independently comprise a H, one or more optionally substituted alkylgroups, lower alkyl groups, alkoxy groups, alkoxyalkyl groups, hydroxygroups, hydroxyalkyl groups, alkenyl groups, amino groups, imino groups,nitrate groups, alkylamino groups, nitroso groups, aryl groups, biarylgroups, bridged aryl groups, fused aryl groups, alkylaryl groups,arylalkyl groups, arylalkoxy groups, arylalkylamino groups, cycloalkylgroups, bridged cycloalkyl groups, cycloalkoxy groups, cycloalkyl-alkylgroups, arylthio groups, alkylthio groups, alkylsulfinyl groups,alkylsulfonyl groups, arylsulfonyl groups, arylsulfinyl groups,caboxamido groups, carbamoyl groups, urea groups, carboxyl groups,carbonyl groups, alkoxycarbonyl groups, halogen groups, haloalkylgroups, haloalkoxy groups, heteroayl, heterocyclic ring,arylheterocyclic ring, heterocyclic compounds, amido, imido, guanidino,hydrazido, aminoxy, alkoxyamino, alkylamido, carboxylic ester groups,thioethers groups, carboxylic acids, phosphoryl groups or combinationthereof; R1, R′1, R″1 independently comprise a C, a N, a O, a S, a H,—CH₂CH₂—, —CH═CH—, —C≡C—, —NH—, —NR—, —NH—NH—, —NH(CH₂)_(n)NH,—NR(CH₂)_(n)NR′— —NR—NR′—, —NH—O—, —NR—O—, —NH(CH₂)_(n)O—,—NR(CH₂)_(n)O—, —NH(CH₂)_(n)S—, —NR(CH₂)_(n)S—, —O(CH₂)_(n)O—,—O(CH₂)_(n)S—, —S(CH₂)_(n)S—, —CO—, —CO₂—, —COS—, —CONH—, —CONR—,—OC(O)NH—, —NHCONH—, —CONHCO—, —CO(CH₂)_(n)CO—, or combination thereof;X comprises a N, a O, a S or 2 Hs; R″6 comprises a C, a N, a P, a S, aH, —CH₂CH₂—, —CH═CH—, —C≡C—, —NH—, —NR—, —NH—NH—, —NH(CH₂)_(n)NH,—NR(CH₂)_(n)NR′— —NR—NR′—, —NH—O—, —NR—O—, —NH(CH₂)_(n)O—,—NR(CH₂)_(n)O—, —NH(CH₂)_(n)S—, —NR(CH₂)_(n)S—, —O(CH₂)_(n)O—,—O(CH₂)_(n)S—, —S(CH₂)_(n)S—, —CO—, —CO₂—, —COS—, —CONH—, —CONR—,—OC(O)NH—, —NHCONH—, —CONHCO—, —CO(CH₂)_(n)CO—, or combination thereof;“A” comprises an acetyl, Boc, 9-fluorenylmethyl carbamate, Cbz, Aloc, anamino acid, an amino acid analogue, an artificial amino acid, adipeptide, a tripeptide, a tetrapeptide, a pentapeptide, a peptidesequence of between 2 and 30 amino acids that have greater than 50%homology to a portion of the GLP-1 sequence SEQ. ID.:1, a linker of 1-20amino acids, a linker of an optionally substituted lower alkyl, a linkerof an optionally substituted C1-C7 alkyl or a combination thereof; and“B” comprises an optionally substituted lower alkyl, an optionallysubstituted C1-C7 alkyl, an amino acid, an amino acid analogue, anartificial amino acid, a dipeptide, a tripeptide, a tetrapeptide, or apentapeptide; a peptide sequence of between 2 and 30 amino acids thathave greater than 50% homology to a portion of the GLP-1 sequence SEQ.ID.:1; a linker of 1-20 amino acids, C1-C7 alkyl or combination thereof,which may also be connected to one or more compounds M1 to M12 of FIG.15, or 19A of FIG. 19.

One example includes a peptidomimetic compound having the formula:

wherein R1, R2, R3, R4 and R5 individually comprise a C, a N, a O, a S,a H, one or more optionally substituted alkyl groups, lower alkylgroups, alkoxy groups, alkoxyalkyl groups, hydroxy groups, hydroxyalkylgroups, alkenyl groups, amino groups, imino groups, nitrate groups,alkylamino groups, nitroso groups, aryl groups, biaryl groups, bridgedaryl groups, fused aryl groups, alkylaryl groups, arylalkyl groups,arylalkoxy groups, arylalkylamino groups, cycloalkyl groups, bridgedcycloalkyl groups, cycloalkoxy groups, cycloalkyl-alkyl groups, arylthiogroups, alkylthio groups, alkylsulfinyl groups, alkylsulfonyl groups,arylsulfonyl groups, arylsulfinyl groups, caboxamido groups, carbamoylgroups, carboxyl groups, carbonyl groups, alkoxycarbonyl groups, halogengroups, haloalkyl groups, haloalkoxy groups, heteroayl, heterocyclicring, arylheterocyclic ring, heterocyclic compounds, amido, imido,guanidino, hydrazido, aminoxy, alkoxyamino, alkylamido, urea groups,carboxylic ester groups, thioethers groups, carboxylic acids, phosphorylgroups or combination thereof, an acetyl, a Boc (t-butoxycarbonyl), aFmoc (9-fluorenylmethoxycarbonyl), a Cbz (benzyloxycarbonyl), an Aloc(allyloxycarbonyl), an amino acid, an amino acid analogue, an artificialamino acid, a dipeptide, a tripeptide, a tetrapeptide, a pentapeptide, alinker of 1-20 amino acids, a linker of an optionally substituted loweralkyl, a linker of an optionally substituted C1-C7 alkyl, a polycyclicaromatic substituted with a OH, a NH₂, a SH, a F, a Cl, a Br, a I, aNHR, a NRR′, a guanidine (CN₃H₄), a N, a O, a S, a H, a peptide sequenceof between 2 and 30 amino acids that has greater than 50% homology to aportion of the GLP-1 sequence SEQ. ID.:1, a linker of 1-20 amino acids,an optionally substituted C1-C7 alkyl or a combination thereof, whichmay also be connected to one or more compounds M1 to M12 of FIG. 15 or19A of FIG. 19. One specific example includes an R1 that is an acetylgroup, R2 that is a benzyl group, R3 and R4 that are 4-fluorobenzylgroups, and R5 that is a methyl group; or where R1 is a t-butoxycarbonylgroup, R2 is a methyl group, R3 is a benzyl group, R4 is a2-naphthylmethyl group, and R5 is a methyl group.

GLP-1 has been found to be effective in lowering blood glucose in abroad range of diabetes states,²⁵ and remarkably, it does not inducehypoglycemia as insulin does.²⁶ It works through a membrane-bound GLP-1Ron many organs, particularly on the pancreatic β-cells, and restoresgrowth and function of β-cells. A GLP-1R agonist discovered from thesaliva of the Gila Monster (i.e., exenatide; developed by Lilly andAmylin)²⁷⁻³⁰ was approved by the FDA for the treatment of Type IIdiabetes³¹. Furthermore, a GLP-1 analogue containing a long fatty acidchain (i.e., liraglutide; developed by Novo Nordisk³²) is currently inphase 3 clinical trials.

Despite the promising results shown by the GLP-1 agonists, these peptidetherapeutics have two main limitations. GLP-1 has a very short half-lifeand is degraded by many enzymes in the serum, especially an ubiquitousenzyme dipeptidyl peptidase-IV (DPP-IV).³³⁻³⁵ DPP-IV cleaves theN-terminal two residues of GLP-1 including His⁷ which is critical forthe biological action of this peptide. By this modification GLP-1 isconverted into an inactive form which may even act as a receptorantagonist³⁶. To prolong the half-life of GLP-1, a number of DPP-IVinhibitors have been developed and showed similar effects as exenatidewith regard to blood glucose regulation. However, DPP-IV inhibitors donot appear to provide the same effect on gastric emptying and weightloss as are induced by GLP-1R agonists, and blocking this widelydistributed enzyme may cause side effects during long-term use.^(37,38)

Another problem of using GLP-1 and its peptide analogues as therapeuticsis introduced by the peptidic structure and relatively high molecularweight of such compounds. Because of these issues, intravenous orsubcutaneous injections are required since peptides are difficult to beformulated for oral delivery. Although intense research has beenundertaken to deliver peptides via oral, transdermal or nasal routes,only limited success has been achieved.^(24,39,40) In addition, thelarge peptidic structure of GLP-1 and its analogues sometimes causes anantibody formation against these molecules, which may prevent long-termclinical use.⁴¹

In contrast to successful precedents that have been reported for smallpeptides like somatostatin and enkephalins,⁵²⁻⁵⁹ developing smallmolecule agonists to mimic larger peptide hormone interactions withcognate GPCRs has proven extremely difficult.^(49,60,61) This issueapplies particularly to class B GPCRs including the GLP-1R, aprototypical member of this receptor subgroup. As common features, classB GPCRs have large N-terminal chains and long extracellular loops whichare believed to constitute multiple and well-separated binding pocketsin the receptors to accommodate cognate large peptideligands.^(49,62,63) The present invention provides synthetic moleculeswhich present the essential functionalities of corresponding peptideligands in the proper three dimensional orientation that enablesspecific receptor interactions, leading to either stimulation orinhibition of receptor-mediated functions.

Peptidomimetics (also known as peptide mimetics) are small organiccompounds which lack the peptide backbone of native peptides. Despitethis modification, they still retain an ability to interact withcorresponding receptors or enzymes by presenting essential chemicalfunctionalities (i.e., pharmacophores) in characteristicthree-dimensional patterns which are complimentary to the targetproteins.^(52,53) Thereby, peptidomimetics potentially combine theadvantages of peptides (e.g., high efficacy and selectivity, low sideeffects) and small organic molecules (e.g., high enzymatic stability andoral bioavailability).

Small molecule agonists have been developed for class A and C GPCRs,however, small molecule agonists for class B GPCRs to which the GLP-1Rbelongs have not been identified prior to the present invention.Although many small molecules were discovered by screening chemicallibraries, most of the reported compounds were found to be antagonistswhich block, rather than induce, signaling.^(2,24,42-49) Although, twosmall molecule agonists for GLP-1R were reported recently,^(50,51) thesemolecules appear to have a different pharmacological profile than GLP-1due to their weak agonist activity. One of these compounds, asubstituted quinoxaline does not compete with GLP-1 for receptorbinding,⁵⁰ suggesting that it may induce receptor activation by adifferent mechanism compared to the endogenous peptide agonist. On theother hand, the other compound that has been reported, a substitutedcyclobutane, appears be an orthosteric agonist and has been shown to beorally active.⁵¹ However, latter type of molecules does not bear anystructural similarity to GLP-1, and it will therefore be difficult topredict possible modifications for optimizing agonist activity.

Generally, despite their high efficacy, all these peptides havedifficulty to be used in vivo since they are susceptible to rapidenzymatic degradation and not orally available. Whereas ligand screeningapproaches have led to the identification of synthetic small moleculeagonists for many class A GPCRs, this strategy has proven much lesssuccessful when applied to class B receptors. In fact, non-peptideligands identified by high-throughput screening for class B GPCRs showno functional activity and are thus classified as antagonists. They areeven allosteric antagonists, not competing with endogenous peptides.Over the years, it was increasingly felt that the complex mechanism ofaction of endogenous peptide agonists at these class B GPCRs isdifficult to be mimicked by such molecules that are typically found inscreening libraries.

Structures of peptide ligands for class B GPCRs have been investigatedby X-ray crystallography and NMR spectroscopy, and found to adoptα-helical structures. In addition, physiological significance of theα-helices in the peptides is also demonstrated by biophysical studiesundertaken in the presence of receptors. To mimic α-helices, the presentinvention provides a new scaffold, oligo-benzamide, that is rigid instructure and place and orient substituents as an α-helix does.Substitution on the rigid tris-benzamide, for instance, allowed easyplacement of three functional groups (R₁₋₃) corresponding to the sidechains of amino acids found at the i, i+4, and i+7 positions of an idealα-helix, representing one helical face as shown in FIG. 1. Furthermore,the present inventors have developed a facile synthetic route to preparea number of tris-benzamides to represent α-helical segments of targetproteins.

GLP-1 contains 30 amino acid residues and includes two helical segmentsthat are connected by a linker region, in addition to a flexibleN-terminal segment. The cognate receptor for this peptide has a longN-terminal chain and large extracellular loops, which together formmultiple GLP-1 binding sites. The complexity of the receptor-ligandinteractions is considered a likely reason why it has been difficult, ifnot impossible, to identify potent peptidomimetics for class B GPCRs byearlier screening campaigns using conventional small molecule libraries.

The present invention provides small molecule GLP-1 agonists thatactivate the GLP-1R selectively. Generally speaking, these compoundsconsist of one or two non-peptide modules which mimic α-helical segmentsof the template peptide in addition to organic linkers and extensionsthat are attached to the helical core modules. It is evident toindividuals who are familiar with this field that compounds with thesame general architecture can be similarly designed to mimic thefunction of other peptide receptor ligands that, like GLP-1, include oneor two helical domains as essential structural features. In particular,this applies to peptides, which interact with other GPCRs within theclass B family since it is well known that very similar principles ofreceptor-peptide ligand interactions apply as have been established forthe GLP-1R. Like GLP-1, each of the corresponding peptide ligandsincludes a C-terminal and an N-terminal helical domain, wherein theligand's C-terminus is primarily involved in receptor recognition andthe N-terminus primarily triggers second messenger signaling. Class BGPCRs to which these general principles apply include, in addition tothe GLP-1R, receptors for glucagon-like peptide-2 (GLP-2), calcitoninand calcitonin receptor-like peptide, corticotropin releasing factor(CRF), gastric inhibitory peptide (GIP), glucagon, growth-hormonereleasing hormone (GHRH), parathyroid hormone (PTH), secretin, pituitaryadenylate cyclase-activating peptide (PACAP), and vasoactive intestinalpolypeptide (VIP). Cognate non-peptide agonists based on the structuresdisclosed in the current application may be therapeutically useful forthe treatment of a broad range of diseases, including but not limited toosteoporosis (PTH receptors), diabetes (GIP receptors), inflammatorybowel disease and short bowel syndrome (GLP-2 receptors), and obesity(calcitonin and calcitonin receptor-like peptide, pituitary adenylatecyclase-activating peptide, and vasoactive intestinal polypeptidereceptors).

Also, it is well known in the field that N-terminal truncations or minorsequence modifications of class B GPCR peptide ligands can convertrespective ligands from agonists (stimulate receptor activity) to eitherantagonists (block ligand-induced function) or inverse agonists(attenuate basal, ligand-independent receptor activity). By inference,slight modifications in corresponding non-peptide mimetics (as disclosedhere) will also lead to a corresponding functional conversion ofbioactivity. For example, resulting antagonist generated by thisapproach would provide useful therapeutics for the treatment of obesity(GIP receptors), diabetes (glucagon receptors) and neuropsychiatric aswell as inflammatory diseases (CRF receptors). Furthermore, resultinginverse agonists would be useful for the treatment of diseases that aretriggered by naturally occurring constitutively active class B GPCRvariants (e.g. dwarfism as a result of previously described PTH mutantsthat show ligand-independent signaling).

The present invention provides small molecule GLP-1 agonists thatactivate GLP-1R selectively. Additionally, present invention providessmall molecules for other peptide hormones for class B GPCRs, e.g., GIP,PTH, secretin, glucagon, VIP, GLP-2, PACAP, GHRH, CRF, and calcitonin.

Although the structure of the GLP-1R (or of any class B GPCR) is not yetavailable, the conformation of GLP-1 (the corresponding agonist peptide)has been studied by 2D-NMR spectroscopy in a solution containingdodecylphosphocholine micelles to provide a membrane-likeenvironment.^(65,66) The 2D-NMR studies showed that GLP-1 has a highlyhelical structure containing two helical segments between residues 13-20and 24-35, covering more than half of the peptide, and a linker regionbetween residues 21-23. Although structures of peptides determined insolution are useful to speculate about receptor-bound conformations, thepresence of receptor proteins can greatly influence peptideconformations upon binding. The highly sophisticated network ofinteractions between receptors and peptides cannot be mimicked properlyby the simple structure of micelles.

To determine a receptor-bound conformation of a large peptide hormone, apositional cyclization scanning method is applied to obtain structuralinformation when a peptide binds to its receptor.⁶⁴ The positionalcyclization scanning method employs a series of conformationallyrestricted peptides and can uncover secondary structures in areceptor-bound conformation. Cyclization of the peptide fixes a definedsecondary structure, and a sequential cyclization scan over the entirepeptide sequence followed by receptor-binding analysis can survey thepresence and location of secondary structure in this molecule. Only acyclic peptide containing a correct secondary structure at the correctposition will be recognized by a receptor with high binding affinity.

The conformational restrictions used in the method are a lactam bridgebetween Lys^(i) and Glu^(i+4) to form an α-helix, or a disulfide bridgebetween Cys⁸ and Cys^(i+5) to stabilize a β-turn.⁶⁷⁻⁷⁰ Although thestructural information obtained does not provide a picture in atomicresolution, it reflects a receptor-bound conformation which is quitedifficult to obtain otherwise. A series of cyclic GLP-1 analoguescontaining lactam bridges between Lys^(i) and Glu^(i+4) were synthesizedto validate the location of α-helices in a receptor-bound conformationof GLP-1. Alpha-helices stabilized between residues 16-21 and 24-34 arewell recognized by the GLP-1R, whereas induction of α-helices near theN-terminus of GLP-1 (residues 11-15) and the putative linker region(residues 21-24) which connects the two helical segments caused poorbinding affinity.

The results from the positional cyclization scanning study and aconformational analysis by NMR consistently indicate the presence of twoseparate α-helices in both the N-terminal regions and C-terminal regionsof GLP-1, and these helices were therefore targeted to design GLP-1peptidomimetics.

FIGS. 1A-1E are images of the structure of α-helix peptidomimeticcompounds. FIG. 1A is an image of the structure of the α-helixpeptidomimetic compounds, FIG. 1B is an image of the general structureof the α-helix peptidomimetic compounds, FIG. 1C is an image of theenergy-minimized structure of an α-helix peptidomimetic compound, FIG.1D is an image of the superimposition of the structure of an α-helixpeptidomimetic (orange) with an α-helix (green), and FIG. 1E is an imageof the structures of the α-helix peptidomimetic compounds 1, 2 and 3.

The present invention provides peptidomimetics representing theα-helices found in GLP-1 using an oligo-benzamide scaffold. As seen inFIG. 1B the substitution on the oligo-benzamide structure allows theplacement of three functional groups corresponding to the amino acids atthe i, i+4, and i+7 positions, representing one face of a helix as canbe seen in FIG. 1A. The structure of the designed α-helix mimeticcompounds was analyzed by molecular modeling using MacroModel⁸⁰ (version9, Schrödinger, New York, N.Y.). A Monte Carlo conformational search wascarried out (5,000 steps) using a MM3 force field⁸¹ implemented into thesoftware. The energy-minimized structure is seen in FIG. 1C anddemonstrates that the three functional groups in the mimetic overlapwell with the corresponding side chains of a helix seen in FIG. 1D.

Based on the positional cyclization scanning and NMR studies of GLP-1,two α-helix mimetic compounds of the present invention (e.g., theα-helix mimetic having structures 1 and 2) were designed to representtwo hydrophobic helical faces located in the N-terminal and C-terminalregions of GLP-1. The N-terminal α-helix mimetic compound havingstructure 1 contains functional groups corresponding to the side chainsof Phe¹², Val¹⁶, and Tyr¹⁹, while the C-terminal α-helix mimeticcompound having structure 2 carries side chain groups corresponding toAla²⁴, Phe²⁸, and Trp³¹ (FIG. 1E).

The α-helix mimetic compounds were prepared in high yields and theirability to interact with the GLP-1R was evaluated. The α-helix mimeticcompounds were dissolved in DMSO to prepare stock solutions with highconcentrations (about 10 mM) with the goal of keeping the final DMSOconcentration in the cell-based assays at 1% or lower. The effect of theDMSO solvent (1%) was evaluated separately and did not show anyappreciable non-specific effects in biological assays.

HEK293 cells stably expressing human GLP-1 receptors were constructedand competitive receptor binding assays of the mimetics were carried outusing ¹²⁵I-exendin(9-39) as a radioligand.⁴⁷ Parallel studies usingtransiently transfected COS-7 cells expressing the human GLP-1R gaveessentially identical results. In addition, cAMP production by themimetics was determined by radioimmunoassay using the transfected HEK293cells to examine agonistic activity. We have also engineered HEK293cells to contain a multimerized cAMP responsive promoter linked toluciferase and beta galactosidase as well as the GLP-1 receptor.

The present invention includes α-helix mimetics compounds and GLP-1analogues containing them seen in FIG. 2, which stimulatedreceptor-mediated cAMP production and consequential luciferase activity,and are classified as agonists. FIGS. 2A and 2B are graphs of thebiological activity of α-helix mimetic compound-containing GLP-1analogues. FIG. 2A is a graph of several α-helix mimeticcompound-containing GLP-1 analogues as well as control peptides(endogeous GLP-1 and fragments of GLP-1) at their concentration of 1 μM.FIG. 2B is a graph of the concentration-response curves of α-helixmimetic compound-containing GLP-1 analogues. It is notable that α-helixmimetic compounds (e.g., SH3) showed high potency especially when theyare conjugated to GLP-1 fragments. It appears that different GLP-1fragments used to connect the α-helix mimetic compound provided a rangeof potency (EC₅₀=134-965 nM). Furthermore, the activity of suchmimetic-peptide conjugates were improved by incorporating a criticalamino acid residue for GLP-1 function, His⁷ (EC₅₀=78 nM).

This function appears to be specific since it could be blocked by aGLP-1R antagonist, exendin(9-39). Furthermore, no compound activity wasdetectable when assessed with untransfected HEK cells (i.e., lackingreceptor expression). This observation further supports the conclusionthat the mimetic compounds act as true GLP-1R agonists. The α-helixmimetic compounds were evaluated for selectivity using COS-7 cellsexpressing GLP-2 receptors, and did not show any cAMP production despiteconsiderable sequence homology of the GLP-1 and GLP-2 receptors. Thisindicated that the mimetics are selective to the GLP-1R and that theα-helix mimetic compounds.

FIGS. 2A and 2B evaluates the α-helix mimicry of GLP-1 by examining theα-helix mimetic compound with structure 1. Several mimetic-peptideconjugates (SH3-GLP-1(22-36), SH3-GLP-1(21-36), and SH3-GLP-1(20-36) inFIG. 2) were created by substitution of a helical segment (residues12-19) in GLP-1(12-36)-NH₂ with the α-helix mimetic having structure 1(or SH3). In addition, two peptides, Ac-GLP-1(22-36)-NH₂ andAc-GLP-1(12-36)-NH₂ were also prepared to serve as controls. The bindingaffinities of the α-helix mimetic-containing GLP-1 analogues are higherthan that of the short control peptide, Ac-GLP-1(22-36)-NH₂. This isexplained by the fact that the mimetic-peptide conjugates includeadditional functional groups found in the helical segment correspondingto GLP-1 residues 12-19, where attachment of the α-helix mimeticcompound having structure 1 mimics the corresponding helical segment. Inluciferase reporter assay, the EC₅₀ of the mimetic-peptide conjugate(SH3-GLP-1(22-36)) was determined to be 134 nM. These findings indicatethat the α-helix mimetics using the oligo-benzamide scaffold cansuccessfully mimic the helical segment of a template peptide.Furthermore, addition of the critical amino acid for GLP-1 function,His⁷, improved the potency (EC₅₀=78 nM).

FIGS. 3A and 3B are helix wheel plots of the residues in GLP-1. FIG. 3Ais a helix wheel plot of the N-terminal and FIG. 3B is a helix wheelplot of the C-terminal helices in GLP-1, with the hydrophobic residuesshown in white whereas hydrophilic ones are shown in grey.

The present invention provides a non-peptide α-helix mimetic compoundwith GLP-1 agonist activity.⁸² The α-helix has a large surface area withmultiple faces created by different sets of residues, whereas themimetic compounds 1 and 2 discussed above represent only two of thesehelical faces. A helical wheel plot was used to visualize theamphiphilic helical faces in GLP-1 thereby guiding the design of theα-helical mimetic compounds. Based on the results from the positionalcyclization scanning and the NMR studies, the two helical sections, onein the N-terminal and the other in the C-terminal region of GLP-1(corresponding to residues 11-20 and 23-34, respectively; see FIG. 3)were selected for mimicry by non-peptide molecules.

As reflected by the helix wheel plots in FIGS. 3A and 3B, an idealα-helix consists of 3.6 residues per complete turn and the angle betweentwo residues in the drawing is therefore chosen to be 100°. Although thehelices in GLP-1 may slightly deviate from the ideal α-helicalstructure, these plots can readily show amino acids on the same helicalface and should thus be targeted to design appropriate α-helix mimeticcompound for GLP-1. The plots demonstrate the amphiphilicity of thehelices in GLP-1 and the hydrophobic and hydrophilic faces that are tobe reiterated in the mimetic compounds.

FIG. 4 is a synthesis scheme to prepare α-helix mimetic compounds of thepresent invention. For example, fifteen α-helix mimetic compounds weremade starting with a 4-amino-3-hydroxybenzoic acid compound 7, which wasconverted to an N—Ac protected methyl ester compound 8. Various alkylgroups were introduced to the hydroxyl group using a variety of alkylhalides and a base (like NaH) known to the skilled artisan. After thealkylation reaction, the methyl ester compound 9 was hydrolyzed usingLiOH, and methyl 4-amino-3-hydroxybenzoate compound 10 was coupled tothe free benzoic acid using a coupling reagent (like BOP), resulting ina benzamide compound 11 containing one alkyl group corresponding to thei position of a helix. These steps were repeated to synthesizeoligo-benzamide compounds.

FIGS. 5A and 5B are images that illustrate various α-helix mimeticcompounds of the present invention. FIG. 5A provides the basic structureindicating the modification locations R1, R2 and R3, which may besubstituted with various groups to provide different characteristics.For example, FIG. 5B is a table of the substitutions at R1, R2 and R3and provides the structures of the α-helix mimetic compounds 13A-13O.The alkylation and coupling reactions were repeated to place two otherfunctional groups corresponding to the i+3 (or i+4) and i+7 positions,to prepare the α-helix mimetic compounds 13A-13O.

Given an α-helix has 3.6 residues per turn, the amino acids on the samehelical face are at the i, i+3 (or i+4) and i+7 positions. Byconsidering this spatial arrangement given by the α-helix mimeticcompound 13, five α-helix mimetic compounds can be designed from theN-terminal helical segment and ten α-helix mimetic compounds can bedesigned from the C-terminal helical segment as seen in FIG. 5B.

The synthesized α-helix mimetic compounds were evaluated byreceptor-binding, cAMP production, and luciferase reporter assays. Theα-helix mimetic compounds were dissolved in DMSO to prepare stocksolutions. Stably transfected HEK cells (or transiently transfected COScells) expressing human GLP-1 receptors were used for competitivereceptor-binding assays using ¹²⁵I-exendin(9-39) as a radioligand.⁴⁷cAMP production by the α-helix mimetic compounds was determined byradioimmunoassay using the transfected HEK cells (or COS cells) toidentify agonists. And, luciferase activity was measured to examinereceptor activation function by agonists. To evaluate selectivity forthe GLP-1R, the α-helix mimetic compounds were tested with GLP-2 andglucagon receptors expressed on transfected cells. The capability of theα-helix mimetic compounds to properly mimic corresponding helicalsegments were examined by preparing mimetic-peptide conjugates in whichone or both helical segments are replaced by α-helix mimetics.

The helical wheel plots of FIG. 3 illustrates that the helical segmentsin GLP-1 are amphiphilic, presenting hydrophobic functional groups onone side and hydrophilic functional groups on the opposite side. Thepresent invention provides amphiphilic α-helix mimetic compounds havingfunctionalities found on both sides of the α-helix to confer higherpotency.

FIGS. 6A-6C are images that illustrates the structures of amphiphilicα-helix mimetics. FIG. 6A is an image of an amphiphilic α-helix mimeticcompound, FIG. 6B is an image of an energy-minimized structure of anamphiphilic α-helix mimetic compound, FIG. 6C is an image of asuperimposition of an amphiphilic α-helix mimetic compound (orange) withan α-helix (green). The helical wheel plots of GLP-1 suggested fiveamphiphilic helix mimetics to represent the N-terminal helical segment.Another five amphiphilic mimetics were designed to represent theC-terminal helical segment.

FIG. 7 is a synthetic scheme for the preparation of amphiphilic α-helixmimetics of the present invention. The present invention providesamphiphilic α-helix mimetic compounds that present functional groups onboth helical faces by modifying a benzamide scaffold and using a3-azido-4-amino-5-hydroxybenzoic acid as a building block as seen inFIG. 7. The hydroxyl group at the 5-position carries a functional groupcorresponding to the side chain at the i+3 (or i+4) or i+7 position onone face of a helix, and the azide at the 3-position is converted to anamine to hold the functional group corresponding to the side chain atthe i+2 or i+5 position on the opposite face of the helix.

In FIG. 7, the synthesis of amphiphilic α-helix mimetics started withbromination of methyl 3-hydroxy-4-aminobenzoate compound 10 followed bydisplacement with an azide. An alkylation reaction using methylN—Ac-4-amino-3-hydroxybenzoate compound 8 and a variety of alkyl halidesand a base like NaH introduced a functional group corresponding to the iposition of the α-helix. The methyl ester compound 16 was hydrolyzed byLiOH, and the methyl 3-azido-4-amino-5-hydroxybenzoate compound 17 wascoupled with BOP. A second alkylation reaction added a functional groupto the free 5-hydroxyl group corresponding to the i+3 (or i+4) position.A Staudinger coupling reaction using a suitable carboxylic acid and PPh₃was used to place a functional group at the i+2 position.⁸⁴ These stepswere repeated to introduce functional groups corresponding to the i+7and i+5 positions in order to complete the synthesis and to produceamphiphilic α-helix mimetic compounds as seen in FIG. 8B compounds21A-21J. The incorporated hydrophilic functional groups not only resultsin a higher potency but also in a higher solubility in water.Corresponding compounds therefore require less organic solvent, which isan advantage for biological evaluation.

FIGS. 8A and 8B illustrate the structures of amphiphilic α-helix mimeticcompounds of the present invention. The general amphiphilic α-helixmimetic structure is given in FIG. 8A and includes groups R1, R2 and R3on one face and groups R4 and R5 on another face of the α-helix. FIG. 8Bis a table of some of the possible substitutions for groups R1, R2, R3,R4 and R5 of the general amphiphilic α-helix mimetic compound given inFIG. 8A. The resulting amphiphilic α-helix mimetic compounds 21A-21Jwere analyzed by molecular modeling using MacroModel⁸⁰ (version 9,Schrodinger, New York, N.Y.), and the five functional groups in theenergy-minimized structure were found to be superimposed well on thecorresponding side chain groups of an ideal α-helix, as seen in FIG. 6C.The amphiphilic α-helix mimetic compounds were examined for receptorbinding and their ability to stimulate cAMP production and luciferaseactivity to identify potent GLP-1 peptidomimetics.

The α-helix mimetic compounds 1 and 2 represent only small segments ofthe entire GLP-1 sequence, and other multifunctional GLP-1peptidomimetics were constructed with the ability of occupying multiplebinding sites in the receptor. For example, His⁷ of GLP-1 is consideredone of the most important amino acids for the function of GLP-1.⁸⁵ Thelack of this amino acid (or its equivalent) in α-helix mimetic compoundscontributes to suboptimal activity.

FIGS. 9A-9E are schematics of the peptide chains of GLP-1 where helicalsegments were sequentially substituted by α-helix mimetic compounds.GLP-1 mimetic compounds were constructed having the C-terminal helicalpeptide segment replaced, the N-terminal helical peptide segmentreplaced, both the C-terminal and the N-terminal helical peptidesegments replaced simultaneously, or the entire GLP-1 peptide sequencereplaced. The GLP-1 mimetic compounds were examined for receptor-bindingaffinity and ability to stimulate cAMP production and luciferaseactivity.

FIG. 9A illustrates the GLP-1 peptide chain 20 having a C-terminus 22and an N-terminus 24. The GLP-1 peptide chain 20 also includes aC-terminal helical peptide segment 26, an N-terminal helical peptidesegment 28 and a His⁷ functional group 30. When the GLP-1 complementaryportions of the peptide chain 20 are attached to an α-helix mimeticcompound, the former provide the missing functional groups that are notpresent in the latter thereby increasing binding affinity to thereceptor, compared to the corresponding α-helix mimetic compound per se.

FIG. 9B illustrates the modified GLP-1 peptide chain 32 that includes aC-terminus 22 and an N-terminus 24. The modified GLP-1 peptide chain 32also includes a C-terminal helical peptide segment 26, an α-helixmimetic moiety 34 and a His⁷ functional group 30. The modified GLP-1peptide chain 32 has the α-helix mimetic 34 incorporated to replace thecorresponding peptide segment in 20.

FIG. 9C illustrates the modified GLP-1 peptide chain 36 that includes aC-terminus 22 and an N-terminus 24. The modified GLP-1 peptide chain 36also includes an α-helix mimetic moiety 38, an N-terminal helicalpeptide segment 28 and a His⁷ functional group 30. The modified GLP-1peptide chain 36 has the α-helix mimetic compound 38 incorporated toreplace the corresponding peptide segment in 20. FIG. 9D illustrates themodified GLP-1 peptide chain 40 that includes a C-terminus 22 and anN-terminus 24. The modified GLP-1 peptide chain 40 also includes aC-terminal α-helix mimetic moiety 38 connected by a linker peptide chain42 to an N-terminal α-helix mimetic moiety 34 and a His⁷ functionalgroup 30. Although the modified GLP-1 peptide chain 40 contains twoα-helix mimetic compounds as well as peptide chains including the His⁷functional group 30 and the linker peptide chain 42, the majority of itssequence is converted into an organic non-peptide structure representedby the two α-helix mimetic compounds.

FIG. 9E illustrates a completely converted GLP-1 peptidomimeticincluding a GLP-1 α-helix mimetic compound 44 having a C-terminus 22 andan N-terminus 24. The GLP-1 mimetic 44 also includes a C-terminalα-helix mimetic moiety 38 connected by a non-peptide chain 46 to anN-terminal α-helix mimetic moiety 34 and a His⁷ analog group. Variousorganic tethers (e.g., w-amino acids in different lengths) were added tocreate a molecule that completely lacks peptide bonds and generallyconserves GLP-1 bioactivity by retaining equivalents of the crucialpharmacophores (in particular, His⁷ and the two α-helices).

One example of the chemical synthesis of the present invention is shownherein; however, the skilled artisan will be able to modify thesynthetic scheme to create different functional groups and create thesame product using different materials. ¹H- and ¹³C-NMR spectra wererecorded on a JEOL Model DELTA-270 (270 MHz) spectrometer.Tetramethylsilane (TMS) was used as the internal standard and thechemical shifts are listed in ppm. Data are expressed as follows:chemical shift (δ), multiplicity (s, singlet; d, doublet; dd, doublet ofdoublet; t, triplet; q, quartet; br s, broad singlet; m, multiplet),coupling constants (Hz). HRMS (FAB) were measured on JEOL HX-110 sector(EB). Silica gel used for column chromatography was Silica Gel StandardGrade (Sorbent Technologies, 230-400 mesh).

A solution of methyl 4-amino-3-hydroxy benzoate compound 7 (5 g, 30.0mmol) and triethylamine (4.6 ml) in 100 ml CH₂Cl₂ was added drop-wise toa solution of di-tert-butyl dicarbonate (7.2 g, 32.9 mmol) in 20 mlCH₂Cl₂ at room temperature. After additional stirring for 12 hours atroom temperature, the mixture was poured into water and extracted withCH₂Cl₂ (3×20 ml). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography (n-Hex/Ethyl Acetate(EA)=9/1 to n-Hex/EA=4/1) to give 7.2 g of compound 22 (90%). ¹H NMR(270 MHz, CDCl₃) δ 1.56 (s, 9H), 3.85 (s, 3H), 4.21 (br s, 2H), 6.74 (d,1H, J=8.42 Hz), 7.73 (dd, 1H, J=8.42, 1.97 Hz), 7.81 (d, 1H, J=1.97 Hz).¹³C NMR (68 MHz, CDCl₃) δ 27.7, 51.9, 84.2, 115.4, 119.9, 124.1, 128.7,137.2, 143.1, 151.3, 166.6. HRMS (FAB): calcd for C₁₃H₁₈NO₅ (M+H)⁺268.1185, found 268.1190.

A solution of phenol compound 22 (0.20 g, 0.75 mmol) and NaH (33 mg in60% oil, 0.82 mmol) in 10 ml dry DMF was stirred for 0.5 hours at roomtemperature and benzyl bromide (0.15 g, 0.82 mmol) was added slowly. Themixture was stirred for an additional hour and poured into water andextracted with ethyl acetate (3×20 ml). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatography(n-Hex/EA=9/1 to n-Hex/EA=4/1) to give 0.22 g of compound 23 (83%). ¹HNMR (270 MHz, CDCl₃) δ 1.52 (s, 9H), 3.89 (s, 3H), 5.16 (s, 2H), 7.27(br s, 1H), 7.35-7.45 (m, 5H), 7.62 (d, 1H, J=1.73 Hz), 7.69 (d, 1H,J=8.40, 1.73 Hz), 8.20 (d, 1H, J=8.40 Hz). ¹³C NMR (68 MHz, CDCl₃) δ28.4, 52.1, 71.1, 81.2, 112.3, 117.1, 123.7, 123.8, 128.0, 128.6, 128.9,133.1, 136.1, 146.1, 152.4, 166.9. HRMS (FAB): calculated for C₂₀H₂₄NO₅(M+H)⁺ 358.1654, found 358.1664.

A solution of phenol compound 22 (0.2 g, 0.75 mmol) and NaH (33 mg in60% oil, 0.82 mmol) in 10 ml dry DMF was stirred for 0.5 hour at roomtemperature and iodomethane (0.12 g, 0.82 mmol) was added slowly and themixture was stirred for an additional hour. The mixture was diluted withwater and extracted with ethyl acetate (3×20 ml). The combined organiclayer was washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography (n-Hex/EA=19/1) to give 0.18 g of compound 24 (86%). ¹HNMR (270 MHz, CDCl₃) δ 1.53 (s, 9H), 3.89 (s, 3H), 3.92 (s, 3H), 7.28(br s, 1H), 7.51 (d, 1H, J=1.73 Hz), 7.67 (dd, 1H, J=8.42, 1.73 Hz),8.17 (d, 1H, J=8.42 Hz). ¹³C NMR (68 MHz, CDCl₃) δ 28.4, 52.0, 55.9,81.0, 110.7, 116.8, 123.5, 123.7, 132.7, 146.9, 152.5, 167.0. HRMS(FAB): calculated for C₁₄H₂₀NO₅ (M+H)⁺ 282.1341, found 282.1336.

A solution of phenol compound 22 (0.2 g, 0.75 mmol) and NaH (33 mg in60% oil, 0.82 mmol) were mixed in 10 ml dry DMF and stirred for 0.5hours at room temperature. Then 2-bromopropane (0.22 g, 1.8 mmol) wasadded slowly and the mixture was stirred for an additional 24 hours,diluted with water and extracted with ethyl acetate (3×20 ml). Thecombined organic layer was washed with brine, dried over Na2SO4,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography (n-Hex/EA=19/1) to give 0.18 g ofcompound 25 (78%). ¹H NMR (270 MHz, CDCl₃) δ 1.40 (d, 6H, J=6.18 Hz),1.55 (s, 9H), 3.89 (s, 3H), 4.70 (septet, 1H, J=6.18 Hz), 7.52 (d, 1H,J=1.73 Hz), 7.63 (dd, 1H, J=8.42, 1.73 Hz), 8.17 (d, 1H, J=8.42 Hz). ¹³CNMR (68 MHz, CDCl₃) δ 22.1, 28.4, 52.0, 71.4, 81.0, 113.0, 116.9, 123.2,123.6, 133.6, 145.0, 152.4, 167.0. HRMS (FAB): calculated for C16H24NO5(M+H)⁺ 310.1654, found 310.1668.

A solution of phenol compound 22 (0.2 g, 0.75 mmol) and NaH (33 mg in60% oil, 0.82 mmol) was stirred in 10 ml dry DMF for 0.5 hour at roomtemperature and then 2-bromobutane (0.25 g, 1.8 mmol) was added slowly.The mixture was stirred for an additional 24 hours, diluted with water,extracted with ethyl acetate (3×20 ml), the combined organic layer waswashed with brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatography(n-Hex/EA=19/1) to give 0.18 g of compound 26 (73%). ¹H NMR (270 MHz,CDCl₃) δ 1.00 (t, 3H, J=7.40), 1.34 (d, 3H, J=6.18 Hz), 1.54 (s, 9H),1.62-1.90 (m, 2H), 3.89 (s, 3H), 4.46 (sextet, 1H, J=6.18 Hz), 7.51 (d,1H, J=1.73 Hz), 7.64 (dd, 1H, J=8.40, 1.73 Hz), 8.17 (d, 1H, J=8.40 Hz).¹³C NMR (68 MHz, CDCl₃) δ 9.9, 19.3, 28.4, 29.2, 52.0, 76.5, 81.0,113.1, 117.0, 123.2, 123.6, 133.6, 145.2, 152.5, 167.0. HRMS (FAB):calculated for C₁₇H₂₆NO₅ (M+H)⁺ 324.1811, found 324.1810.

A solution of phenol compound 22 (0.2 g, 0.75 mmol) and NaH (33 mg in60% oil, 0.82 mmol) was stirred in 10 ml dry DMF for 0.5 hours at roomtemperature and 2-bromomethylnaphtalene (0.18 g, 0.82 mmol) was addedslowly. The mixture was stirred for an additional hour. The mixture wasdiluted with water, extracted with ethyl acetate (3×20 ml), and thecombined organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography (n-Hex/EA=10/1 to n-Hex/EA=4/1) togive 0.25 g of compound 27 (82%). ¹H NMR (270 MHz, CDCl₃) δ 1.50 (s,9H), 3.87 (s, 3H), 5.30 (s, 2H), 7.30 (br s, 1H), 7.48-7.57 (m, 3H),7.65-7.73 (m, 2H), 7.82-7.94 (m, 4H), 8.22 (d, 1H, J=8.40 Hz). ¹³C NMR(68 MHz, CDCl₃) δ 28.4, 52.1, 71.3, 81.2, 112.4, 117.1, 123.8, 123.9,125.5, 126.5, 126.6, 127.1, 127.9, 128.1, 128.8, 133.1, 133.3, 133.5,146.2, 152.4, 166.9. HRMS (FAB): calculated for C₂₄H₂₆NO₅ (M+H)⁺408.1811, found 408.1833.

To a solution of compound 23 (2 g, 5.60 mmol) in 16 ml CH₂Cl₂, 4 mltrifluoroacetic acid was added in an ice-water bath. The reactionsolution was stirred at room temperature for 2 hours and the excesstrifluoroacetic acid and CH₂Cl₂ were removed under reduced pressure. Theresidue was dissolved in CH₂Cl₂, washed with saturated NaHCO₃ and brineand dried over Na₂SO₄. The organic layer was concentrated under reducedpressure to give the corresponding aniline, which was used in the nextstep without purification. A solution of aniline and DMAP (68 mg, 0.56mmol) in acetic anhydride was stirred at room temperature for 12 hours.The reaction mixture was poured into water and extracted with CH₂Cl₂.The organic layer was washed with 1N HCl, water, and saturated NaHCO₃solution, dried and concentrated to give compounds 28 and 29. Themixture was purified by column chromatography (n-Hex/EA=4/1 ton-Hex/EA=2/1) to give 1.62 g of compound 29 (97%). ¹H NMR (270 MHz,CDCl₃) δ 2.17 (s, 3H), 3.89 (s, 3H), 5.16 (s, 2H), 7.36-7.46 (m, 5H),7.65 (d, 1H, J=1.73 Hz), 7.69 (dd, 1H, J=8.40, 1.73 Hz), 7.92 (br s,1H), 8.48 (d, 1H, J=8.67 Hz). ¹³C NMR (68 MHz, CDCl₃) δ 25.1, 52.2,71.3, 112.4, 118.9, 123.8, 125.0, 128.0, 128.7, 128.9, 132.4, 135.9,146.4, 166.7, 168.5. HRMS (FAB): calculated for C₁₇H₁₈NO₄ (M+H)⁺300.1236, found 300.1235.

Compound 29 (1.62 g, 5.68 mmol) was dissolved in 1N NaOH (10 ml)/MeOH(20 ml)/THF (40 ml) and stirred at 60° C. for 2 hours. Methanol and THFwere carefully concentrated and the mixture was acidified with 1N HCl,and the suspension was extracted with ethyl acetate, dried over Na₂SO₄and evaporated under reduced pressure to give the corresponding acid,which was used in the next step without purification. The solution ofacid, DMF (cat.) and SOCl₂ (2.7 g, 22.7 mmol) in 20 ml THF was heated at60° C. for 2 hours. After the reaction mixture was cooled, the reactionmixture was concentrated under reduced pressure. The residue wasdissolved in CH₂Cl₂ and cooled at 0° C. To this acid chloride DIPEA(5.14 g, 39.8 mmol) and methyl 4-amino-3-hydroxybenzoate compound 7(1.42 g, 8.51 mmol) were added and stirred at room temperature for 2hours. The reaction mixture was concentrated under reduced pressure andthe residue was purified by column chromatography (n-Hex/EA=2/1 ton-Hex/EA=1/1) to give 2.02 g of compound 30 (82% in three steps). ¹H NMR(270 MHz, CDCl₃) δ 2.20 (s, 3H), 3.85 (s, 3H), 4.11 (br s, 2H), 5.20 (s,2H), 6.80 (d, 1H, J=8.91 Hz), 7.36-7.47 (m, 5H), 7.74-7.82 (m, 3H), 7.88(dd, 1H, J=8.42, 1.73 Hz), 7.99 (br s, 1H), 8.56 (d, 1H, J=8.42 Hz). ¹³CNMR (68 MHz, CDCl₃) δ 25.2, 51.9, 71.4, 112.9, 115.6, 119.0, 120.3,123.5, 124.59, 124.63, 128.0, 128.8, 128.9, 129.0, 133.4, 135.7, 136.9,143.3, 146.5, 164.1, 166.6, 168.7. HRMS (FAB): calculated for C₂₄H₂₃N₂O₆(M+H)⁺ 435.1556, found 435.1568.

A solution of phenol compound 30 (1.93 g, 4.44 mmol) and NaH (0.20 g in60% oil, 4.88 mmol) in 50 ml dry DMF was stirred for 0.5 hour at roomtemperature and then 4-fluorobenzyl bromide (1.01 g, 5.33 mmol) wasadded slowly. The mixture was stirred for an additional 2 hours, dilutedwith water, and extracted with ethyl acetate (3×40 ml). The combinedorganic layer was washed with brine, dried (Na₂SO₄) and concentratedunder reduced pressure. The residue was purified by columnchromatography (n-Hex/EA=4/1 to n-Hex/EA=2/1) to give 1.86 g of compound31 (77%). ¹H NMR (270 MHz, CDCl₃) δ 2.18 (s, 3H), 3.91 (s, 3H), 5.11 (s,2H), 5.17 (s, 2H), 7.09 (t, 2H, J=8.42 Hz), 7.27 (dd, 1H, J=8.64, 1.73Hz), 7.35-7.48 (m, 7H), 7.57 (d, 1H, J=1.73 Hz), 7.67 (d, 1H, J=1.73Hz), 7.75 (dd, 1H, J=8.42, 1.73 Hz), 8.46 (d, 1H, J=8.42 Hz), 8.62 (d,1H, J=8.64 Hz), 8.72 (br s, 1H). ¹³C NMR (68 MHz, CDCl₃) δ 25.1, 52.2,70.8, 71.3, 111.0, 112.4, 116.0 (d, J=21.3 Hz), 118.8, 119.1, 119.6,124.1, 125.1, 128.0, 128.8, 129.0, 129.4, 129.8 (d, J=8.3 Hz), 131.7,132.5, 135.7, 146.7, 147.1, 162.9 (d, J=248.1 Hz), 164.5, 166.7, 168.6.HRMS (FAB): calculated for C₃₁H₂₈FN₂O₆ (M+H)⁺ 543.1931, found 543.1942.

Dimer compound 31 (1.86 g, 3.43 mmol) was dissolved in 1N NaOH (10ml)/MeOH (20 ml)/THF (40 ml) and heated at 60° C. for 2 hours. Methanoland THF were carefully concentrated and the mixture was acidified with1N HCl, and the suspension was extracted with ethyl acetate, dried overNa₂SO₄ and evaporated under reduced pressure to give the correspondingacid, which was used in the next step without purification. The solutionof acid, BOP (1.92 g, 4.11 mmol) and DIPEA (1.11 g, 8.57 mmol) in CH₂Cl₂was stirred at 0° C. for 0.5 hour. Methyl 4-amino-3-hydroxybenzoatecompound 7 (0.57 g, 2.86 mmol) was added and stirred at room temperaturefor 2 hours. The mixture was poured into water and extracted with CH₂Cl₂(3×40 ml), and the combined organic layer was washed with brine, driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by column chromatography (dichloromethane/ethylether=19/1) to give 1.72 g of compound 32 (74% in two steps). ¹H NMR(270 MHz, CDCl₃) δ 2.19 (s, 3H), 3.85 (s, 3H), 4.15 (br s, 2H), 5.19 (s,2H), 5.20 (s, 2H), 6.82 (d, 2H, J=8.88 Hz), 7.10 (t, 2H, J=8.65 Hz),7.30 (dd, 1H, J=8.40, 1.73 Hz), 7.34-7.50 (m, 7H), 7.59 (d, 1H, J=1.73Hz), 7.75-7.81 (m, 3H), 7.88 (m, 1H), 8.48 (d, 1H, J=8.40 Hz), 8.70 (d,1H, J=8.40 Hz), 8.79 (br s, 1H). ¹³C NMR (68 MHz, CDCl₃) δ 25.1, 51.9,70.9, 71.3, 111.1, 112.9, 115.6, 116.1 (d, J=21.8 Hz), 119.0, 119.1,119.6, 120.4, 123.6, 124.7, 124.8, 128.0, 128.8, 129.0, 129.3, 129.8 (d,J=8.3 Hz), 131.5 (d, J=3.6 Hz), 131.8, 133.5, 135.7, 136.9, 143.2,146.9, 147.1, 162.7 (d, J=216.4 Hz), 164.1, 164.5, 166.6, 168.6. HRMS(FAB): calculated for C₃₈H₃₃FN₃O₈ (M+H)⁺ 678.2252, found 678.2262.

A solution of phenol compound 32 (1.72 g, 2.54 mmol) and NaH (0.11 g in60% oil, 2.79 mol) in 50 ml dry DMF was stirred for 0.5 hours at roomtemperature and then 4-fluorobenzyl bromide (3.05 mmol) was addedslowly. The mixture was stirred for an additional 2 hours. The mixturewas diluted with water and extracted into ethyl acetate (3×40 ml). Thecombined organic layer was washed with brine, dried (Na₂SO₄) andconcentrated under reduced pressure. The residue was purified by columnchromatography (dichloromethane/ethyl ether=19/1) to give 1.20 g ofcompound 33 (61%). ¹H NMR (270 MHz, DMSO-d6) δ 2.15 (s, 3H), 3.86 (s,3H), 5.23 (s, 2H), 5.27 (s, 2H), 5.29 (s, 2H), 7.12-7.74 (m, 19H),8.03-8.15 (m, 3H), 9.34 (br s, 1H), 9.51 (br s, 1H), 9.59 (br s, 1H) ¹³CNMR (68 MHz, CDCl₃) δ 24.6, 52.7, 70.1, 70.6, 112.4, 112.5, 113.6, 115.8(d, J=21.8 Hz), 120.8, 120.9, 121.8, 123.0, 123.1, 123.4, 126.5, 128.0,128.5, 129.0, 130.0, 130.3 (d, J=7.8 Hz), 131.2, 131.5, 132.0, 132.7,133.38, 133.42, 133.48, 137.2, 148.6, 149.9, 150.1, 162.4 (d, J=243.4Hz), 164.9, 166.4, 169.5. HRMS (FAB): calculated for C₄₅H₃₈F₂N₃O₈ (M+H)⁺786.2627, found 786.2598.

Compound 24 (2 g, 7.11 mmol) was dissolved in 1N NaOH (10 ml)/MeOH (20ml)/THF (40 ml) and heated at 60oC for 2 hours. Methanol and THF werecarefully concentrated and the mixture was acidified with 1N HCl. Thesuspension was extracted with ethyl acetate, dried over Na2SO4 andevaporated under reduced pressure to give the corresponding acid, whichwas used in the next step without purification. The solution of acid,DMF (cat.) and SOCl2 (3.38 g, 28.4 mmol) in 20 ml THF was heated at 60oCfor 2 hours. The reaction mixture was cooled and concentrated underreduced pressure. The residue was dissolved in CH₂Cl₂ and cooled at 0°C. To this acid chloride DIPEA (9.19 g, 71.1 mmol) and methyl4-amino-3-hydroxybenzoate compound 7 (1.42 g, 8.53 mmol) were added andstirred at room temperature for 2 hours. The reaction mixture wasconcentrated under reduced pressure and purified by columnchromatography (n-Hex/EA=4/1 to n-Hex/EA=2/1) to give 2.28 g of compound34 (77% in three steps). ¹H NMR (270 MHz, CDCl₃) δ 1.55 (s, 3H), 3.84(s, 3H), 3.95 (s, 3H), 4.16 (br s, 2H), 6.80 (d, 1H, J=8.88 Hz), 7.37(br s, 1H), 7.63 (d, 1H, J=1.73 Hz), 7.74-7.82 (m, 2H), 7.85 (dd, 1H,J=8.42, 1.73 Hz), 8.56 (d, 1H, J=8.67 Hz). ¹³C NMR (68 MHz, CDCl₃) δ28.4, 51.8, 56.1, 81.3, 111.2, 115.6, 116.9, 120.2, 122.1, 124.4, 124.7,128.8, 133.8, 137.0, 143.4, 147.1, 152.3, 164.4, 166.6. HRMS (FAB):calculated for C₂₁H₂₅N₂O₇ (M+H)⁺ 417.1662, found 417.1645.

A solution of compound 34 (2.28 g, 5.48 mmol) and NaH (0.24 g in 60%oil, 6.02 mol) in 50 ml dry DMF was stirred for 0.5 hour at roomtemperature and benzyl bromide (1.13 g, 6.57 mmol) was added slowly. Themixture was stirred for an additional 2 hours, diluted with water andextracted with ethyl acetate (3×40 ml). The combined organic layer waswashed with brine, dried (Na₂SO₄) and concentrated under reducedpressure. The residue was purified by column chromatography(n-Hex/EA=4/1 to n-Hex/EA=2/1) to give 2.21 g of compound 35 (80%). ¹HNMR (270 MHz, CDCl₃) δ 1.54 (s, 3H), 3.84 (s, 3H), 3.92 (s, 3H), 5.20(s, 2H), 7.24-7.52 (m, 8H), 7.71 (d, 1H, J=1.73 Hz), 7.77 (dd, 1H,J=8.42, 1.73 Hz), 8.13 (d, 1H, J=8.42 Hz), 8.65 (d, 1H, J=8.67 Hz), 8.78(br s, 1H). ¹³C NMR (68 MHz, CDCl₃) δ 28.4, 52.2, 55.9, 71.5, 81.1,109.3, 112.3, 117.0, 118.6, 119.6, 124.0, 125.0, 128.0, 128.1, 128.8,129.0, 132.0, 132.7, 135.9, 146.9, 147.5, 152.4, 164.7, 166.8. HRMS(FAB): calculated for C₂₈H₃₁N₂O₇ (M+H)⁺ 507.2131, found 507.2133.

Compound 35 (2.21 g, 4.49 mmol) was dissolved in 1N NaOH (10 ml)/MeOH(20 ml)/THF (40 ml) and heated at 60oC for 2 hours. Methanol and THFwere carefully concentrated and the mixture was acidified with 1N HCl.The suspension was extracted with ethyl acetate, dried over Na2SO4 andevaporated under reduced pressure to give the corresponding acid, whichwas used in the next step without purification. The solution of acid,DMF (cat.) and SOCl2 (2.14 g, 17.9 mmol) in 20 ml THF was refluxed for 2hours. The reaction mixture was cooled and concentrated under reducedpressure. The residue was dissolved in CH₂Cl₂ and cooled at 0oC. To thisacid chloride, DIPEA (5.80 g, 44.9 mmol) and methyl4-amino-3-hydroxybenzoate 5 (0.90 g, 5.38 mmol) were added and stirredat room temperature for 2 hours. The reaction mixture was concentratedunder reduced pressure and purified by column chromatography(n-Hex/EA=9/1 to n-Hex/EA=2/1) to give 2.19 g of compound 36 (76% inthree steps). ¹H NMR (270 MHz, CDCl₃) δ 1.55 (s, 3H), 3.86 (s, 6H), 5.24(s, 3H), 6.82 (d, 1H, J=6.87 Hz), 7.78-7.86 (m, 3H), 7.69 (dd, 1H,J=8.67, 1.73 Hz), 8.15 (d, 1H, J=8.42 Hz), 8.73 (d, 1H, J=8.64 Hz), 8.85(br s, 1H). ¹³C NMR (68 MHz, CDCl₃) δ 28.4, 51.9, 55.9, 71.6, 81.2,109.3, 112.8, 115.6, 117.0, 118.8, 119.6, 120.2, 123.4, 124.7, 124.8,127.9, 128.0, 128.9, 129.0, 132.2, 133.6, 135.7, 136.9, 143.4, 147.0,147.5, 152.4, 164.2, 164.7, 166.6. HRMS (FAB): calculated for C₃₅H₃₆N₃O₉(M+H)⁺ 642.2452, found 642.2432.

A solution of trimer compound 36 (2.19 g, 3.41 mmol) and NaH (0.15 g in60% oil, 3.75 mmol) in 50 ml dry DMF was stirred for 0.5 hour at roomtemperature. 2-bromomethyl naphthalene (0.91 g, 4.10 mmol) was addedslowly to the solution. The solution was stirred for an additional 2hours, diluted with water and extracted with ethyl acetate (3×40 ml).The combined organic layer was washed with brine, dried (Na2SO4) andconcentrated under reduced pressure. The residue was purified by columnchromatography (n-Hex/EA=4/1 to n-Hex/EA=1/1) to give 2.29 g of compound37 (86%). ¹H NMR (270 MHz, CDCl₃) δ 1.55 (s, 3H), 3.82 (s, 3H), 3.91 (s,3H), 5.03 (s, 2H), 5.37 (s, 2H), 7.22-7.60 (m, 13H), 7.74-7.94 (m, 6H),8.11 (d, 1H, J=8.40 Hz), 8.58 (d, 1H, J=8.40 Hz), 8.66 (d, 1H, J=8.40Hz), 8.70 (br s, 1H), 8.84 (br s, 1H). ¹³C NMR (68 MHz, CDCl₃) δ 28.5,52.4, 56.0, 71.5, 71.9, 81.3, 109.3, 110.8, 112.6, 117.1, 118.9, 119.0,119.8, 120.2, 124.2, 125.3, 126.8, 126.9, 127.2, 128.1, 128.2, 129.0,129.1, 129.4, 132.1, 132.2, 132.8, 133.4, 133.5, 135.9, 147.1, 147.5,147.6, 152.6, 164.6, 164.8, 166.9. HRMS (FAB): calculated for C₄₆H₄₄N₃O₉(M+H)⁺ 782.3078, found 782.3065.

The synthesis of benzamides includes an alkylation reaction to place afunctional group corresponding to an amino acid in a helix. The reactionis given below:

The hydroxyl group in methyl 4-(t-butoxycarbonylamino)-3-hydroxybenzoatewas reacted with a series of alkyl halides in the presence of bases asdescribed in Table 1.

Product R—X Reaction Condition Yield (%)^(a) 2a

K₂CO₃ (1.2 eq), acetone, reflux, 24 h 33 2a

NaH (1.1 eq), DMF, rt, 1.5 h 83 2a

NaH (1.1 eq), THF, reflux, 2.5 h 53 2a

NaOMe (1.2 eq), DMF, rt, 1.5 h 73 2a

NaOMe (1.2 eq), THF, reflux, 2.5 h 72 2a

DBU (5 eq), DMF, rt, 12 h 19 2b CH₃I NaH (1.1 eq), DMF, rt, 1.5 h 86 2c

NaH (1.1 eq), DMF, rt, 24 h 78 2d

NaH (1.1 eq), DMF, rt, 24 h 73 2e

NaH (1.1 eq), DMF, rt, 1.5 h 83

Several bases and solvents were screened to optimize the reactioncondition and the use of NaH in DMF at room temperature resulted in highyield. Sodium methoxide also provided good yield and less byproductsthan NaH, whereas K₂CO₃ and a hindered organic base,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were found to be inefficient.As a solvent, DMF appears to be more effective than THF since thebenzylation in THF required refluxing even with the most efficient basefound (NaH), whereas DMF provided higher yield at much lower ambienttemperature. The alkylation reaction was carried out with various alkylhalides under the optimized reaction condition, resulting in the desiredproducts in high yield (70-80%). Methyl and benzyl halides mimicking Alaand Phe, respectively, gave slightly better yields compared to aliphaticalkyl halides, such as 2-bromopropane and 2-bromobutane representing Valand Ile, respectively. 2-Naphthylmethyl group was introduced in anattempt to replace the indole side chain of Trp. The coupling reactionwas performed using an unalkylated hydroxybenzoate instead of thealkylated. Using SOCl₂ or BOP as a coupling reagent, the alkoxybenzamidewas synthesized in high yield (70-80%), and a subsequent alkylationproduced the desired dialkoxybenzamide which possesses two functionalgroups in a helix.

FIG. 10 is a scheme for the synthesis of two tris-benzamides 48A and48B, where tris-benzamides 48A includes a R1 that is an Acetyl (Ac)group, R2 is a Benzyl (Bn) group and R3 and R4 are 4-fluorobenzyl groupsand tris-benzamides 48B includes a R1 is a t-butoxycarbonyl (Boc) group,R2 is a Methyl (Me) group and R3 is a Benzyl (Bn) group and R4 is a2-naphthylmethyl.

After the alkylation of the hydroxybenzoate compound 50, the methylester was hydrolyzed using NaOH, and methyl 4-amino-3-hydroxybenzoatewas coupled to the benzoic acid (compound 52A where R1 is an Acetyl (Ac)group and R2 as a Benzyl (Bn) group and compound 52B where R1 as at-butyloxycarbonyl (Boc) group and R2 as a Methyl (Me) group) usingSOCl₂, resulting in a bis-benzamide containing one alkyl group (compound54A where R1 as an Acetyl (Ac) group and R2 as a Benzyl (Bn) group andcompound 54B where R1 as a t-butyloxycarbonyl (Boc) group and R2 as aMethyl (Me) group) corresponding to the i position of a helix. Thealkylation and coupling reactions were repeated twice to place two otherfunctional groups corresponding to the i+4 (or i+3) and i+7 positions asseen in compound 56A where R1 is an Acetyl (Ac) group, R2 is a Benzyl(Bn) group and R3 is a 4-fluorobenzyl group; compound 56B where R1 is at-butyloxycarbonyl (Boc) group, R2 is a Methyl (Me) group and R3 is aBenzyl (Bn) group; compound 58A where R1 is an Acetyl (Ac) group, R2 isa Benzyl (Bn) group and R3 is a 4-fluorobenzyl group; and compound 58Bwhere R1 is a t-butoxycarbonyl (Boc) group, R2 is a Methyl (Me) groupand R3 is a Benzyl (Bn) group.

The present invention also provides an amphiphilic α-helix mimetic usinga different template. The template used to mimic an amphiphilic α-helix,is a bis-benzamide structure that constitutes two4-amino-2,5-dihydroxybenzoic acid moieties as seen in FIGS. 11A and 11B.Analogous to the building block of the original amphiphilic α-helixmimetic (3,4-diamino-5-hydroxybenzoic acid), the building block of thealternative scaffold (4-amino-2,5-dihydroxybenzoic acid) also has twohydroxyl groups at the 2- and 5-positions to present two functionalgroups found on opposite faces of an α-helix. However, the structure ofthe alternative scaffold is quite different compared to the originalone. Its structure was again analyzed by molecular modeling usingMacroModel (a Monte Carlo conformational search).

FIG. 11C is an image of the energy minimized structure of the lowestenergy conformation was analyzed by molecular modeling using MacroModel.The energy minimized structure of the lowest energy conformation showedsignificantly enhanced rigidity in the structure, resulting from twohydrogen bonds made by the benzamide proton and two nearby alkoxy groups(R2 and R3), one from the 2-position in the upper benzene ring and theother from the 5-position in the lower benzene ring. These hydrogenbonds tightly secure the relative orientation of two benzene rings, anddirect two alkyl groups (R2 and R3) at the 2-position in the upper ringand the 5-position in the lower ring on the same side of the structure.This results in the remaining two alkyl groups (R1 and R4) at the5-position in the upper ring and the 2-position in the lower ring beingon the same side, opposite to the former two groups (R2 and R3).Superimposition of this alternative amphiphilic α-helix mimetic over anα-helix reveals that 4 alkyl groups (R1-4) in the mimetic represent 4side chains of the helix extremely well as seen in FIG. 11C. Thehydrogen bonds increase the distance between two alkyl groups (R1 andR4) at the 5-position in the upper ring and the 2-position in the lowerring, well representing the i and i+7 positions. On the other hand, thetwo alkyl groups (R2 and R3) being in close proximity due to thehydrogen bonds overlay well to the side chain groups at the i+2 and i+5positions on the opposite face of a helix.

FIG. 12 is a scheme for the synthesis of the alternative amphiphilicα-helix mimetics of the present invention. The 4-aminosalicylic acidcompound 60 was protected as N-Boc methyl ester compound 62, which wasoxidized with persulfate. The Boyland-Sim oxidation reaction producedmethyl N-Boc-4-amino-2,5-dihydroxybenzoate compound 62, and the N-Bocprotecting group was removed by TFA. Then, the 4-amino and 5-hydroxylgroups were protected as a ketal by the treatment of2,2-dimethoxypropane. After the 4-amino group of the building blockcompound was acetylated, an alkyl group (R1) was introduced to the free5-hydroxyl group using various alkyl halides and a base (NaH or NaOMe)for the side chain functionality at the i position. Subsequently, theketal was removed by an acidic treatment and a second alkylationreaction was carried out to place a functional group (R2) for the i+2position. The second building block (compound 64) was coupled using BOPor PyBrOP to form a bis-benzamide. The steps (alkylation, deprotection,and another alkylation) were repeated to prepare the compounds 64, 66,68 and 70.

For example, the present invention includes an oligo-benzamidepeptidomimetic compound having the following formula:

wherein X is independently a C, a N, a O, a S, a H, —CH₂CH₂—, —CH═CH—,—C≡C—, —NH—, —NR—, —NH—NH—, —NH(CH₂)_(n)NH, —NR(CH₂)_(n)NR′— —NR—NR′—,—NH—O—, —NR—O—, —NH(CH₂)_(n)O—, —NR(CH₂)_(n)O—, —NH(CH₂)_(n)S—,—NR(CH₂)_(n)S—, —O(CH₂)_(n)O—, —O(CH₂)_(n)S—, —S(CH₂)_(n)S—, —CO—,—CO₂—, —COS—, —CONH—, —CONR—, —OC(O)NH—, —NHCONH—, —CONHCO—,—CO(CH₂)_(n)CO—, or combination thereof; wherein Y is independently a N,a O, a S or 2 Hs; wherein R1, R2, R3, R4, R′1, R′2, R′3, R′4, R″1, R″2,R″3, and R″4, comprise independently a H, optionally substituted alkyl,lower alkyl, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, alkenyl, amino,imino, nitrate, alkylamino, dialkylamino, nitro, nitroso, aryl, biaryl,polycyclic aromatic, alkylaryl, arylalkyl, arylalkoxy, arylalkylamino,cycloalkyl, bridged cycloalkyl, cycloalkoxy, cycloalkyl-alkyl, arylthio,alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, arylsulfinyl,caboxamido, carbamoyl, carboxyl, carbonyl, alkoxycarbonyl, halogen,haloalkyl, haloalkoxy, heteroayl, heterocyclic ring, arylheterocyclicring, heterocyclic compounds, amido, imido, guanidino, hydrazido,aminoxy, alkoxyamino, alkylamido, urea, carboxylic ester, thioethers,carboxylic acids, phosphoryl groups, polycyclic aromatic substitutedwith a OH, NH₂, SH, F, Cl, Br, I, NHR, NRR′, CN₃H₄, a N, a O, a S, a H,or combination thereof. And, n is 0, 1, 2, 3, 4, 5, 6, 7 etc. Forexample R1, R2, R3, R4, R′1, R′2, R′3, R′4, R″1, R″2, R″3, and R″4, mayinclude independently one or more of the structures listed in FIG. 13,where Z is a OH, NH₂, SH, F, Cl, Br or I; W is a OH, OR, NH₂, NHR, NRR′or CN₃H₄; n is 0, 1, 2, 3, 4, 5, 6, 7 etc.; and Y is a N, a O, a S or 2Hs.

“A” may be a substituent (R1, R2, R3, R4, R′1, R′2, R′3, R′4, R″1, R″2,R″3, or R″4), an acetyl, Boc (t-butoxycarbonyl), a Fmoc(9-fluorenylmethoxycarbonyl), a Cbz (benzyloxycarbonyl), an Aloc(allyloxycarbonyl), an amino acid, an amino acid analogue, an artificialamino acid, a dipeptide, a tripeptide, a tetrapeptide, or apentapeptide. “A” may be a peptide sequence of between 2 and 30 aminoacids that has greater than 50% homology to a portion of the GLP-1sequence SEQ. ID.:1. FIG. 14 is the sequence of GLP-1 from amino acid 7to amino acid 36. “A” may be a linker of 1-20 amino acids, an optionallysubstituted lower alkyl, an optionally substituted C₁-C₇ alkyl, a linkeras listed below:

or a combination thereof.

“B” may be a substituent (R1, R2, R3, R4, R′1, R′2, R′3, R′4, R″1, R″2,R″3, or R″4), an optionally substituted alkyl, lower alkyl, anoptionally substituted C1-C7 alkyl, an amino acid, an amino acidanalogue, an artificial amino acid, a dipeptide, a tripeptide, atetrapeptide, or a pentapeptide; a peptide sequence of between 2 and 30amino acids that has greater than 50% homology to a portion of the GLP-1sequence SEQ. ID.:1 (FIG. 14); a linker of 1-20 amino acids, anoptionally substituted C1-C7 alkyl or a linker as listed below:

or a combination thereof, which may be optionally connected to one ormore of the compounds M1-M12 listed in FIG. 15, or 19A of FIG. 19; or acombinations thereof.

FIGS. 16A-16K are images that illustrate various α-helix mimeticcompounds of the present invention. FIGS. 16A-16C provide generalstructures indicating examples of the modification to the bonds thatlink the individual benzamides. FIGS. 16D-16K are images that illustratevarious α-helix mimetic compounds of the present invention. Thisprovides the basic structure indicating examples of the locations on therings that may be substituted with various groups to provide differentcharacteristics. In addition, R may individually be substituted withvarious groups to provide different characteristics, e.g., optionallysubstituted alkyl, lower alkyl, C1-C7 alkyl, alkoxy groups, lower alkylgroups, alkoxy groups, alkoxyalkyl groups, hydroxy groups, hydroxyalkylgroups, alkenyl groups, amino groups, imino groups, nitrate groups,alkylamino groups, nitroso groups, aryl groups, biaryl groups, bridgedaryl groups, fused aryl groups, alkylaryl groups, arylalkyl groups,arylalkoxy groups, arylalkylamino groups, cycloalkyl groups, bridgedcycloalkyl groups, cycloalkoxy groups, cycloalkyl-alkyl groups, arylthiogroups, alkylthio groups, alkylsulfinyl groups, alkylsulfonyl groups,arylsulfonyl groups, arylsulfinyl groups, caboxamido groups, carbamoylgroups, urea groups, carboxyl groups, carbonyl groups, alkoxycarbonylgroups, halogen groups, haloalkyl groups, haloalkoxy groups, heteroayl,heterocyclic ring, arylheterocyclic ring, heterocyclic compounds, amido,imido, guanidino, hydrazido, aminoxy, alkoxyamino, alkylamido,carboxylic ester groups, thioethers groups, carboxylic acids, phosphorylgroups or a combination thereof. For example, R may includeindependently one or more of the structures listed in FIG. 13, where Zis a OH, NH₂, SH, F, Cl, Br or I; W is a OH, OR, NH₂, NHR, NRR′ orCN₃H₄; n is 0, 1, 2, 3, 4, 5, 6, 7 etc.; and Y is a N, a O, a S or 2 Hs.

FIGS. 17A-17M are images that illustrate various α-helix mimeticcompounds of the present invention. FIGS. 17A-17B provide the generalstructures indicating examples of the modification to the bonds thatlink the 2 individual benzamides. FIGS. 17C-17E provide specificexamples of the general structure of the modification to the bonds thatlink the individual benzamides. FIGS. 17F-17M are images that illustratevarious α-helix mimetic compounds of the present invention. Thisprovides the basic structure indicating examples of the locations on therings that may be substituted with various groups to provide differentcharacteristics. In addition, R may individually be substituted withvarious groups to provide different characteristics, e.g., R may beoptionally substituted alkyl, lower alkyl, C1-C7 alkyl, alkoxy groups,lower alkyl groups, alkoxy groups, alkoxyalkyl groups, hydroxy groups,hydroxyalkyl groups, alkenyl groups, amino groups, imino groups, nitrategroups, alkylamino groups, nitroso groups, aryl groups, biaryl groups,bridged aryl groups, fused aryl groups, alkylaryl groups, arylalkylgroups, arylalkoxy groups, arylalkylamino groups, cycloalkyl groups,bridged cycloalkyl groups, cycloalkoxy groups, cycloalkyl-alkyl groups,arylthio groups, alkylthio groups, alkylsulfinyl groups, alkylsulfonylgroups, arylsulfonyl groups, arylsulfinyl groups, caboxamido groups,carbamoyl groups, carboxyl groups, carbonyl groups, alkoxycarbonylgroups, urea groups, halogen groups, haloalkyl groups, haloalkoxygroups, heteroayl, heterocyclic ring, arylheterocyclic ring,heterocyclic compounds, amido, imido, guanidino, hydrazido, aminoxy,alkoxyamino, alkylamido, carboxylic ester groups, thioethers groups,carboxylic acids, phosphoryl groups or combination thereof. For example,R may include independently one or more of the structures listed in FIG.13, where Z is a OH, NH₂, SH, F, Cl, Br or I; W is a OH, OR, NH₂, NHR,NRR′ or CN₃H₄; n is 0, 1, 2, 3, 4, 5, 6, 7 and so forth; and Y is a N, aO, a S or 2 Hs.

FIGS. 18A-18K provide specific examples of the structure of the variousindividual α-helix mimetic compounds of the present invention. FIGS.18A-18K provide the general structure of the compound with the R grouppositions indicated. The table lists the compound numbers 100-960 andindicates the functional groups at each R group on the general structureof the α-helix mimetic compound to provide different characteristics.

FIGS. 19A-19E are images that illustrate various α-helix mimeticcompounds of the present invention. FIG. 19A provides the generalstructure of the α-helix mimetic compounds. X may independently be a C,a N, a O, a S, a H, —CH₂CH₂—, —CH═CH—, —C≡C—, —NH—, —NR—, —NH—NH—,—NH(CH₂)_(n)NH, —NR(CH₂)_(n)NR′— —NR—NR′—, —NH—O—, —NR—O—,—NH(CH₂)_(n)O—, —NR(CH₂)_(n)O—, —NH(CH₂)_(n)S—, —NR(CH₂)_(n)S—,—O(CH₂)_(n)O—, —O(CH₂)_(n)S—, —S(CH₂)_(n)S—, —CO—, —CO₂—, —COS—, —CONH—,—CONR—, —OC(O)NH—, —NHCONH—, —CONHCO—, —CO(CH₂)_(n)CO—, or combinationthereof; and Y may be independently a N, a O, a S or 2 H's. And, n is 0,1, 2, 3, 4, 5, 6, 7 etc. R1, R2, R3, R4, R′1, R′2, R′3, R′4, R″1, R″2,R″3, and R″4, comprise independently a H, optionally substituted alkyl,lower alkyl, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, alkenyl, amino,imino, nitrate, alkylamino, dialkylamino, nitro, nitroso, aryl, biaryl,polycyclic aromatic, alkylaryl, arylalkyl, arylalkoxy, arylalkylamino,cycloalkyl, bridged cycloalkyl, cycloalkoxy, cycloalkyl-alkyl, arylthio,alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, arylsulfinyl,caboxamido, carbamoyl, carboxyl, carbonyl, alkoxycarbonyl, halogen,haloalkyl, haloalkoxy, heteroayl, heterocyclic ring, arylheterocyclicring, heterocyclic compounds, amido, imido, guanidino, hydrazido,aminoxy, alkoxyamino, alkylamido, urea, carboxylic ester, thioethers,carboxylic acids, phosphoryl groups, polycyclic aromatic substitutedwith a OH, NH₂, SH, F, Cl, Br, I, NHR, NRR′, CN₃H₄, a N, a O, a S, a H,or combination thereof. FIGS. 19B-19E provide several specific examplesof the general structure. The compositions of the present invention maybe an agonist, an inverse agonist, an antagonist, a partial agonist, apartial antagonist, a co-agonist or a combination thereof depending onthe receptor and the functional groups of the composition.

It is contemplated that any embodiment discussed in this specificationcan be implemented with respect to any method, kit, reagent, orcomposition of the invention, and vice versa. Furthermore, compositionsof the invention can be used to achieve methods of the invention.

It will be understood that particular embodiments described herein areshown by way of illustration and not as limitations of the invention.The principal features of this invention can be employed in variousembodiments without departing from the scope of the invention. Thoseskilled in the art will recognize, or be able to ascertain using no morethan routine experimentation, numerous equivalents to the specificprocedures described herein. Such equivalents are considered to bewithin the scope of this invention and are covered by the claims.

All publications and patent applications mentioned in the specificationare indicative of the level of skill of those skilled in the art towhich this invention pertains. All publications and patent applicationsare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

The use of the word “a” or “an” when used in conjunction with the term“comprising” in the claims and/or the specification may mean “one,” butit is also consistent with the meaning of “one or more,” “at least one,”and “one or more than one.” The use of the term “or” in the claims isused to mean “and/or” unless explicitly indicated to refer toalternatives only or the alternatives are mutually exclusive, althoughthe disclosure supports a definition that refers to only alternativesand “and/or.” Throughout this application, the term “about” is used toindicate that a value includes the inherent variation of error for thedevice, the method being employed to determine the value, or thevariation that exists among the study subjects.

As used in this specification and claim(s), the words “comprising” (andany form of comprising, such as “comprise” and “comprises”), “having”(and any form of having, such as “have” and “has”), “including” (and anyform of including, such as “includes” and “include”) or “containing”(and any form of containing, such as “contains” and “contain”) areinclusive or open-ended and do not exclude additional, unrecitedelements or method steps.

The term “or combinations thereof” as used herein refers to allpermutations and combinations of the listed items preceding the term.For example, “A, B, C, or combinations thereof” is intended to includeat least one of: A, B, C, AB, AC, BC, or ABC, and if order is importantin a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB.Continuing with this example, expressly included are combinations thatcontain repeats of one or more item or term, such as BB, AAA, MB, BBC,AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan willunderstand that typically there is no limit on the number of items orterms in any combination, unless otherwise apparent from the context.

All of the compositions and/or methods disclosed and claimed herein canbe made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of preferred embodiments, it will beapparent to those of skill in the art that variations may be applied tothe compositions and/or methods and in the steps or in the sequence ofsteps of the method described herein without departing from the concept,spirit and scope of the invention. All such similar substitutes andmodifications apparent to those skilled in the art are deemed to bewithin the spirit, scope and concept of the invention as defined by theappended claims.

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1. A method for treating diseases related to a peptide hormone receptorin a subject by administering to the subject a tris-benzamidepeptidomimetic compound comprising three optionally substitutedbenzamides and a peptide hormone receptor binding peptide, wherein thetris-benzamide peptidomimetic compound binds to a peptide hormonereceptor.
 2. The method of claim 1, wherein the peptide hormone receptorcomprises a class B G-protein coupled receptor.
 3. The method of claim2, wherein the class B G-protein coupled receptor is selected from aglucagon-like peptide-1 (GLP-1) receptor, glucagon receptor,glucagon-like peptide-2 (GLP-2) receptor, GIP receptor, PTH receptor,CRF receptor, calcitonin receptor, secretin receptor, VIP receptor,PACAP receptor, and GHRH receptor.
 4. The method of claim 1, wherein thetris-benzamide peptidomimetic compound comprising the formula:

wherein R1, R2, and R3, independently comprise a H, one or moreoptionally substituted alkyl groups, lower alkyl groups, alkoxy groups,alkoxyalkyl groups, hydroxy groups, hydroxyalkyl groups, alkenyl groups,amino groups, imino groups, nitrate groups, alkylamino groups, nitrosogroups, aryl groups, biaryl groups, bridged aryl groups, fused arylgroups, alkylaryl groups, arylalkyl groups, arylalkoxy groups,arylalkylamino groups, cycloalkyl groups, bridged cycloalkyl groups,cycloalkoxy groups, cycloalkyl-alkyl groups, arylthio groups, alkylthiogroups, alkylsulfinyl groups, alkylsulfonyl groups, arylsulfonyl groups,arylsulfinyl groups, caboxamido groups, carbamoyl groups, carboxylgroups, carbonyl groups, alkoxycarbonyl groups, halogen groups,haloalkyl groups, haloalkoxy groups, heteroayl, heterocyclic ring,arylheterocyclic ring, heterocyclic compounds, amido, imido, guanidino,alkylamido, carboxylic ester groups, thioethers groups, carboxylicacids, phosphoryl groups, polycyclic aromatic substituted with a OH,NH₂, SH, F, Cl, Br, I, NHR, NRR′, CN₃H₄, a N, a O, a S, a H, orcombination thereof; “A” comprises an acetyl, a Boc (t-butoxycarbonyl),a Fmoc (9-fluorenylmethoxycarbonyl), a Cbz (benzyloxycarbonyl), an Aloc(allyloxycarbonyl), an amino acid, an amino acid analogue, an artificialamino acid, a peptide sequence of between 2 and 30 amino acids that havegreater than 50% homology to a portion of the GLP-1 sequence SEQ. ID.NO.:1, and “B” comprises an optionally substituted lower alkyl, anoptionally substituted C1-C7 alkyl, an amino acid, an amino acidanalogue, an artificial amino acid, or a portion of the GLP-1 sequenceSEQ. ID. NO.:1.
 5. A method for modifying glucose metabolism in asubject comprising the steps of: administering to the subject atris-benzamide peptidomimetic compound comprising at three optionallysubstituted benzamides and a peptide hormone receptor binding peptide,wherein administering the tris-benzamide peptidomimetic compoundmodifies glucose metabolism by modifying one or more of hyperglycemia,insulin resistance, obesity, hyperlipidemia, or hyperlipoproteinemia. 6.The method of claim 5, wherein the optional substitution of the at threeoptionally substituted benzamides comprise an optionally substitutedgroup selected from an alkyl, a lower alkyl, an alkoxy, an alkoxyalkyl,a hydroxy, a hydroxyalkyl, an alkenyl, an amino, an imino, a nitrate, analkylamino, a dialkylamino, a nitro, a nitroso, an aryl, a biaryl, apolycyclic aromatic, an alkylaryl, an arylalkyl, an arylalkoxy, anarylalkylamino, a cycloalkyl, a bridged cycloalkyl, a cycloalkoxy, acycloalkyl-alkyl, an arylthio, an alkylthio, an alkylsulfinyl, analkylsulfonyl, an arylsulfonyl, an arylsulfinyl, a caboxamido, acarbamoyl, a carboxyl, a carbonyl, an alkoxycarbonyl, a halogen, ahaloalkyl, a haloalkoxy, a heteroayl, a heterocyclic ring, anarylheterocyclic ring, a heterocyclic compounds, an amido, an imido, aguanidino, an alkylamido, a carboxylic ester, a thioether, a carboxylicacid, a phosphoryl group, polycyclic aromatic substituted with a OH,NH₂, SH, F, Cl, Br, I, NHR, NRR′, CN₃H₄, a N, a O, a S, a H, and acombination thereof.
 7. The method of claim 5, wherein thetris-benzamide peptidomimetic compound comprises the formula:

wherein R1, R2, R3, R4 and R5 individually comprise a C, a N, a O, a S,a H, one or more optionally substituted alkyl groups, lower alkylgroups, alkoxy groups, alkoxyalkyl groups, hydroxy groups, hydroxyalkylgroups, alkenyl groups, amino groups, imino groups, nitrate groups,alkylamino groups, nitroso groups, aryl groups, biaryl groups, bridgedaryl groups, fused aryl groups, alkylaryl groups, arylalkyl groups,arylalkoxy groups, arylalkylamino groups, cycloalkyl groups, bridgedcycloalkyl groups, cycloalkoxy groups, cycloalkyl-alkyl groups, arylthiogroups, alkylthio groups, alkylsulfinyl groups, alkylsulfonyl groups,arylsulfonyl groups, arylsulfinyl groups, caboxamido groups, carbamoylgroups, carboxyl groups, carbonyl groups, alkoxycarbonyl groups, halogengroups, haloalkyl groups, haloalkoxy groups, heteroayl, heterocyclicring, arylheterocyclic ring, heterocyclic compounds, amido, imido,guanidino, alkylamido, carboxylic ester groups, thioethers groups,carboxylic acids, phosphoryl groups or combination thereof; an acetyl,Boc (t-butoxycarbonyl), a Fmoc (9-fluorenylmethoxycarbonyl), a Cbz(benzyloxycarbonyl), an Aloc (allyloxycarbonyl), an amino acid, an aminoacid analogue, an artificial amino acid, a peptide sequence of between 2and 30 amino acids that have greater than 50% homology to a portion ofthe GLP-1 sequence SEQ. ID. NO.:1.
 8. The method of claim 7, wherein R1,R2, R3, and R4 may individually comprise a H, an acetyl group or at-butoxycarbonyl group, a Fmoc group, a Cbz group, an Aloc group, abenzyl group, a methyl group, a substituted benzyl group, a4-fluorobenzyl group or a 2-naphthylmethyl group.
 9. A method fortreating a subject that would medically benefit from either stimulationor inhibition of a peptide hormone receptor comprising the steps of:administering to the subject a tris-benzamide peptidomimetic compoundthat functions as an agonist, an antagonist, an inverse agonist or acombination thereof, wherein the tris-benzamide peptidomimetic compoundcomprises three optionally substituted benzamides and a peptide hormonereceptor binding peptide, wherein each of the three optionallysubstituted benzamides are optionally substituted on a benzene ring withone substitution, wherein each of the substitutions individuallycomprise one or more optionally substituted groups selected from analkyl, a lower alkyl, an alkoxy, an alkoxyalkyl, a hydroxy, ahydroxyalkyl, an alkenyl, an amino, an imino, a nitrate, an alkylamino,a dialkylamino, a nitro, a nitroso, an aryl, a biaryl, a polycyclicaromatic, an alkylaryl, an arylalkyl, an arylalkoxy, an arylalkylamino,a cycloalkyl, a bridged cycloalkyl, a cycloalkoxy, a cycloalkyl-alkyl,an arylthio, an alkylthio, an alkylsulfinyl, an alkylsulfonyl, anarylsulfonyl, an arylsulfinyl, a caboxamido, a carbamoyl, a carboxyl, acarbonyl, an alkoxycarbonyl, a halogen, a haloalkyl, a haloalkoxy, aheteroayl, a heterocyclic ring, an arylheterocyclic ring, a heterocycliccompounds, an amido, an imido, a guanidino, an alkylamido, a carboxylicester, a thioether, a carboxylic acid, a phosphoryl group, polycyclicaromatic substituted with a OH, NH₂, SH, F, Cl, Br, I, NHR, NRR′, CN₃H₄,a N, a O, a S, a H, or a combination thereof.
 10. The method of claims9, wherein one of the one or more substitutions correspond to an iposition, one of the one or more substitutions correspond to an i+3position or an i+4 position, and one of the one or more substitutionscorrespond to an i+7 position of an α-helix.
 11. The method of claim 9,wherein the pharmaceutical peptidomimetic compound is adapted for oral,dermatological, transdermal or parenteral administration.
 12. The methodof claim 9, further comprising one or more of diluents excipients,active agents, lubricants, preservatives, stabilizers, wetting agents,emulsifiers, salts for influencing osmotic pressure, buffers, colorings,flavorings, aromatic substances, penetration enhancers, surfactants,fatty acids, bile salts, chelating agents, colloids and combinationsthereof.
 13. A tris-benzamide peptidomimetic composition that binds to aclass B G-protein coupled receptor comprising the formula:

wherein R1, R2, R3, R4 and R5 individually comprise a C, a N, a O, a S,a H, one or more optionally substituted alkyl groups, lower alkylgroups, alkoxy groups, alkoxyalkyl groups, hydroxy groups, hydroxyalkylgroups, alkenyl groups, amino groups, imino groups, nitrate groups,alkylamino groups, nitroso groups, aryl groups, biaryl groups, bridgedaryl groups, fused aryl groups, alkylaryl groups, arylalkyl groups,arylalkoxy groups, arylalkylamino groups, cycloalkyl groups, bridgedcycloalkyl groups, cycloalkoxy groups, cycloalkyl-alkyl groups, arylthiogroups, alkylthio groups, alkylsulfinyl groups, alkylsulfonyl groups,arylsulfonyl groups, arylsulfinyl groups, caboxamido groups, carbamoylgroups, carboxyl groups, carbonyl groups, alkoxycarbonyl groups, halogengroups, haloalkyl groups, haloalkoxy groups, heteroayl, heterocyclicring, arylheterocyclic ring, heterocyclic compounds, amido, imido,guanidino, alkylamido, carboxylic ester groups, thioethers groups,carboxylic acids, phosphoryl groups or combination thereof an acetyl,Boc (t-butoxycarbonyl), a Fmoc (9-fluorenylmethoxycarbonyl), a Cbz(benzyloxycarbonyl), an Aloc (allyloxycarbonyl), an amino acid, an aminoacid analogue, an artificial amino acid, a peptide sequence of between 2and 30 amino acids that have greater than 50% homology to a portion ofthe GLP-1 sequence SEQ. ID. NO.:1; and wherein at least one groupselected from R1, R2, R3, R4 and R5 comprise at least a portion of aclass B G-protein coupled receptor protein.
 14. The tris-benzamidepeptidomimetic composition of claim 13, wherein the at least a portionof a class B G-protein coupled receptor comprises at least a portion ofa GLP-1 sequence SEQ. ID. NO.:1.
 15. The tris-benzamide peptidomimeticcomposition of claim 13, wherein R1 comprises an acetyl group, R2comprises a benzyl group, R3 and R4 comprise 4-fluorobenzyl groups, andR5 comprises a peptide chain corresponding to GLP-1(22-36) amide. 16.The tris-benzamide peptidomimetic composition of claim 13, wherein R1comprises a t-butoxycarbonyl group, R2 comprises a methyl group, R3comprises a benzyl group, R4 comprises a 2-naphthylmethyl group, and R5comprises a peptide chain corresponding to GLP-1(22-36) amide.
 17. Thetris-benzamide peptidomimetic composition of claim 13, wherein R1comprises a dipeptide (His-Gly), R2 comprises a benzyl group, R3comprises an isopropyl, and R4 comprises a 4-fluorobenzyl group, and R5comprises a peptide chain corresponding to GLP-1(22-36) amide.
 18. Thetris-benzamide peptidomimetic composition of claim 13, wherein R1comprises a histidine, R2 comprises a benzyl group, R3 comprises anisopropyl, and R4 comprises a 4-fluorobenzyl group, and R5 comprises apeptide chain corresponding to GLP-1(22-36) amide.
 19. Thetris-benzamide peptidomimetic composition of claim 13, wherein R1comprises an acetyl group, R2 comprises a benzyl group, R3 comprises anisopropyl group, R4 comprises 4-fluorobenzyl group, and R5 comprises apeptide chain corresponding to GLP-1(22-36) amide.
 20. Thetris-benzamide peptidomimetic composition of claim 13, wherein R1, R2,R3, and R4 may individually comprise a H, an acetyl group or at-butoxycarbonyl group, a Fmoc group, a Cbz group, an Aloc group, abenzyl group, a methyl group, a substituted benzyl group, a4-fluorobenzyl group or a 2-naphthylmethyl group.
 21. A compoundcomprising the formula:

wherein R1, R2, R3, R4 R5, R6, R7, R8, and R9 individually comprise a C,a N, a O, a S, a H, optionally substituted alkyl groups, lower alkylgroups, alkoxy groups, alkoxyalkyl groups, hydroxy groups, hydroxyalkylgroups, alkenyl groups, amino groups, imino groups, urea groups, nitrategroups, alkylamino groups, nitroso groups, aryl groups, biaryl groups,bridged aryl groups, fused aryl groups, alkylaryl groups, arylalkylgroups, arylalkoxy groups, arylalkylamino groups, cycloalkyl groups,bridged cycloalkyl groups, cycloalkoxy groups, cycloalkyl-alkyl groups,arylthio groups, alkylthio groups, alkylsulfinyl groups, alkylsulfonylgroups, arylsulfonyl groups, arylsulfinyl groups, caboxamido groups,carbamoyl groups, carboxyl groups, carbonyl groups, alkoxycarbonylgroups, halogen groups, haloalkyl groups, haloalkoxy groups, heteroayl,heterocyclic ring, arylheterocyclic ring, heterocyclic compounds, amido,imido, guanidino, hydrazido, aminoxy, alkoxyamino, alkylamido,carboxylic ester groups, thioethers groups, carboxylic acids, phosphorylgroups, polycyclic aromatic, substituted polycyclic aromatic, an acetyl,Boc (t-butoxycarbonyl), a Fmoc (9-fluorenylmethoxycarbonyl), a Cbz(benzyloxycarbonyl), an Aloc (allyloxycarbonyl), an amino acid, an aminoacid analogue, an artificial amino acid, a dipeptide, a tripeptide, atetrapeptide, a pentapeptide a linker of 1-30 amino acids, a linker ofan optionally substituted lower alkyl, a linker of an optionallysubstituted C1-C7 alkyl, a polycyclic aromatic substituted with a OH, aNH₂, a SH, a F, a Cl, a Br, a I, a NHR, a NRR′, a CN₃H₄, a N, a O, a S,a H, a linker of 1-30 amino acids, an optionally substituted C1-C7alkyl, an optionally substituted linker as seen below

wherein X and Y independently comprises a N, a O, a C, a S, or a H andwherein at least one group selected from R1, R2, R3, R4, R5, R6, R7, R8,and R9 comprise at least a portion of a class B G-protein coupledreceptor protein.